Abstract:
The present invention provides a pharmaceutical composition of gabapentin wherein lactam level remains below 0.5% even after more than two years of storage at 25 to 30° C. and 60% relative humidity.

Description:
FIELD OF INVENTION 
       [0001]    This invention is concerned with stable gabapentin compositions. More particularly, this invention is concerned with pharmaceutical compositions comprising a therapeutically effective amount of gabapentin and an excipient which is not detrimental to the long-term stability of gabapentin. 
       BACKGROUND OF THE INVENTION 
       [0002]    Gabapentin (I) and its pharmaceutically acceptable salts have been used for a number of years for the treatment of cerebral disorders such as epilepsy, fainting attacks, hypokinesis and cranial traumas, has been known for many years, for example as disclosed in U.S. Pat. No. 4,024,175, U.S. Pat. No. 4,087,544 and U.S. Pat. No. 4894476. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    U.S. Pat. No. 6,054,482 discloses that the preparation and long-term storage of gabapentin and its pharmaceutically acceptable salts present problems since (i) during the preparation the compounds show considerable variations without apparent reason; (ii) very pure gabapentin, when stored long term, shows differing stabilities; and (iii) a toxic lactam (II) is formed when the gabapentin degrades. Pharmaceutically acceptable gabapentin compositions must comprise no more than 0.5% by weight of this toxic lactam compound. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    To combat lactam formation and provide long-term stability in pharmaceutical compositions, US-A-6054482 teaches that the following procedures must be maintained: 
         [0003]    1. The active gabapentin materials must be prepared as highly purified, non-derivatized free amino acids, for example from the corresponding hydrochloride by ion exchange. The proportion of remaining hydrochloride admixtures, or anions of other mineral acids, should thereby not exceed 20 ppm; 
         [0004]    2. To suppress the formation of toxic lactam, a particular excipient must be used. 
         [0005]    Under the above storage conditions generally applicable for medicaments, toxic lactam formation does not increase within a period of time of 1 year after production of the pharmaceutical composition or of the active material by more than 0.2% by wt and preferably 0.1% by wt, based on the weight of the pure active material. 
         [0006]    In addition, U.S. Pat. No. 6,054,482 provides a specific list of excipient materials which do not influence the stability of the active gabapentin compound when the proportion of mineral acid does not exceed 20 ppm. These are: hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, crospovidone, poloxamer 407, poloxamer 188, sodium starch glycolate, copolyvidone, maize starch, cyclodextrin, lactose, talc as well as co-polymers of dimethylamino-methacrylic acid and neutral methacrylic acid ester. It also provides a specific list of excipient materials which reduce the stability of the active gabapentin compounds: these are modified maize starch, sodium croscarmellose, glycerol behenic acid ester, methacrylic acid co-polymers (types A and C), anion exchangers, titanium dioxide, and silica gels such as Aerosil 200. 
         [0007]    U.S. Pat. No. 6,531,509 discloses that the long-term stability of pharmaceutical compositions based on active gabapentin compounds is not affected by the nature of the excipient materials disclosed in U.S. Pat. No. 6,054,482 provided that the amount of mineral acid anion in the composition is in excess of 20 ppm. 
         [0008]    It is desired that pharmaceutical compositions are very stable, so that they can be offered for sale with very long shelf lives. It is also preferred that stable, pharmaceutically active compositions are not limited to pre-determined amounts of mineral acid anion. 
         [0009]    Neither U.S. Pat. No. 6,054,482 nor U.S. Pat. No. 6,531,509 suggest that the compositions disclosed therein may be stable for very long periods e.g. for at least two years, irrespective of the amount of mineral acid anion or excipient. 
         [0010]    We now report pharmaceutically effective gabapentin compositions which are stable for very long periods of time i.e. compositions to contain less than 0.5% lactam after at least two years of storage at 25° C. and 60% atmospheric humidity. Stability results for different durations and temperatures are included hereinafter. 
       SUMMARY OF THE INVENTION 
       [0011]    Accordingly, the present invention provides a stable pharmaceutical composition of gabapentin, stable in storage for extended periods, under conditions selected from the ranges consisting of: storage for at least 3 years at 25° C. and 60% relative humidity, storage for at least 2 years at 30° C. and 60% relative humidity, and storage for at least 6 months at 40° C. and 75% relative humidity. 
         [0012]    According to another aspect of the present invention there is provided a pharmaceutical composition comprising gabapentin and microcrystalline cellulose as the sole excipient. Alternatively, the composition also comprises a lubricant, such as magnesium stearate. 
         [0013]    According to another aspect of the present invention there is provided a pharmaceutical composition comprising gabapentin and microcrystalline cellulose as the sole diluent. 
         [0014]    Preferably the composition is in the form of a capsule. 
         [0015]    Preferably the capsule comprises hard gelatin. 
         [0016]    Preferably the composition of the hard gelatin capsule further comprises one or more of: methyl hydroxy benzoate; propyl hydroxyl benzoate, titanium oxide, yellow iron oxide, red iron oxide, in any suitable combinations. The composition of the gelatin capsule may also contain purified water. 
         [0017]    According to another aspect of the present invention there is provided a pharmaceutical composition comprising gabapentin and excipients including microcrystalline cellulose and magnesium stearate. Preferably, these are the only excipients, in which case microcrystalline cellulose is regarded as a diluent and magnesium stearate as a lubricant. 
         [0018]    According to another aspect of the present invention there is provided a pharmaceutical composition comprising gabapentin and one or more of the following as a diluent: dibasic calcium phosphate; tribasic calcium phosphate; calcium sulphate; mannitol; microcrystalline cellulose; starch; and lactose. 
         [0019]    According to another aspect of the present invention there is provided a pharmaceutical composition comprising gabapentin and one or more of the following as a lubricant: magnesium stearate; stearic acid; and colloidal silicon dioxide. 
         [0020]    According to another aspect of the present invention there is provided a pharmaceutical composition comprising gabapentin and sodium lauryl sulphate. 
         [0021]    According to another aspect of the present invention there is provided a pharmaceutical composition comprising gabapentin, the composition further comprising: 
         [0022]    (i) microcrystalline cellulose; 
         [0023]    (ii) magnesium stearate; and 
         [0024]    (iii) sodium lauryl sulphate. 
         [0025]    In certain embodiments, this composition also contains colloidal silicon dioxide. 
         [0026]    The content of mineral acid anions may be less than 70 ppm, and more preferably less than 50 ppm or 30 ppm. These ranges are not intended to be limiting and contents outside these ranges can be used. 
     
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Table Titles 
       [0027]    Table 1: Composition of the proprietary medical product 
         [0028]    Table 2: Stability Specification and routine tests for Gabapentin Capsules 
         [0029]    Table 3: Details of batches put on stability 
         [0030]    Table 4: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/100) stored at 25° C.±2° C./60%±5% RH 
         [0031]    Table 5: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/100) stored at 30° C±2° C./60%±5% RH 
         [0032]    Table 6: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/100) stored at 40° C.±2° C./ 75%±5% RH 
         [0033]    Table 7: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/100) stored at 25° C.±2° C./60%±5% RH 
         [0034]    Table 8: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/100) stored at 30° C.±2° C./60%±5% RH 
         [0035]    Table 9: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/100) stored at 40° C.±2° C./75%±5% RH 
         [0036]    Table 10: Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/300) stored at 25° C.±2° C./60%±5% RH 
         [0037]    Table 11: Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/300) stored at 30° C.±2° C./60%±5% RH 
         [0038]    Table 12: Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/300) stored at 30° C.±2° C./60%±5% RH 
         [0039]    Table 13: Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/300) stored at 25° C.±2° C./ 60%±5% RH 
         [0040]    Table 14: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/400) stored at 25° C.±2° C./60%±5% RH 
         [0041]    Table 15: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/400) stored at 30° C.±2° C./60%±5% RH 
         [0042]    Table 16: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I1/400) stored at 40° C.±2° C./75%±5% RH 
         [0043]    Table 17: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/400) stored at 25° C.±2° C./60%±5% RH 
         [0044]    Table 18: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II1/400) stored at 30° C.±2 ° C./60%±5% RH 
         [0045]    Table 19: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/400) stored at 40° C.±2° C./75%±5% RH 
         [0046]    Table 20: Stability of Neurontin® Capsules 400 mg stored in PVC/PVdC/Aluminium packs stored at 25° C.±2° C. /60%±5% RH 
         [0047]    Table 21: Stability of Neurontin® Capsules 400 mg stored in PVC/PVdC/Aluminium packs stored at 30° C.±2° C./60%±5% RH 
         [0048]    Table 22: Stability of Neurontin® Capsules 400 mg stored in PVC/PVdC/Aluminium packs stored at 40° C.±2° C./75%±5% RH 
         [0049]    Table 23: Excipients used in the pre-formulation studies 
         [0050]    Table 24: Trial blends for pre-formulation studies. 
         [0051]    Table 25: Pre-formulation studies, Batch Number: GD 
         [0052]    Table 26: Pre-formulation studies, Batch Number: GD2 
         [0053]    Table 27: Pre-formulation studies, Batch Number: GD3 
         [0054]    Table 28: Pre-formulation studies, Batch Number: GD4 
         [0055]    Table 29: Pre-formulation studies, Batch Number: GD5 
         [0056]    Table 30: Pre-formulation studies, Batch Number: GD6 
         [0057]    Table 31: Pre-formulation studies, Batch Number: GD7 
         [0058]    Table 32: Pre-formulation studies, Batch Number: GL1 
         [0059]    Table 33: Pre-formulation studies, Batch Number: GL2 
         [0060]    Table 34: Pre-formulation studies, Batch Number: GL3 
         [0061]    Table 35: Pre-formulation studies, Batch Number: GS1 
         [0062]    Table 36: Pre-formulation studies, Blend I 
         [0063]    Table 37: Pre-formulation studies, Blend II 
         [0064]    Table 38: Pre-formulation studies, Neurontin® Capsules 400 mg, Batch Number: 015077 
         [0065]    Table 39: Pre-formulation studies, Drug Substance, Gabapentin Lot number: R 90562 
         [0066]    The invention shall now be described further by way of exemplification. 
       Experimental Protocols 
       [0067]    HPLC Assay for Related Substances 
         [0068]    Chromatographic Conditions 
       Column 
       [0069]    YMC—ODS—AQ, 5 μm, 250 mm×4.6 or equivalent 
       Column Temperature 
       [0070]    Ambient 
       Mobile Phase 
       [0071]    0.025 M Potassium Phosphate Monobasic (pH 6.0): Methanol (70:30) 
       Detector 
       [0072]    UV at 210 nm 
       Flow Rate 
       [0073]    10 ml/minute 
       Injection Volume 
       [0074]    50 μl 
       Run Time 
       [0075]    10 minutes or as appropriate for Standard Solution 
         [0076]    15 minutes or as appropriate for Resolution Solution 
         [0077]    70 minutes or as appropriate for Lactam Marker, Test Solution and Diluent Solutions. 
       Needle Wash Solution 
       [0078]    Water:methanol (70:30) 
       Mobile Phase Preparation 
       [0079]    0.025M potassium phosphate, monobasic (KH 2 PO 4 ) buffer solution pH 6.0: Weight about 6.8 g of potassium phosphate, monobasic (KH 2 PO 4 ) and dissolve in about 1800 ml of water. Adjust pH of the solution to 6.0 (±0.05) using 1 N Sodium Hydroxide solution. Add sufficient water to make 2000 ml and mix well. 
         [0080]    Mobile Phase: Mix 1400 ml of 0.025 M potassium phosphate, monobasic (KH 2 PO 4 ) buffer solution pH 6.0 with 600 ml methanol, filter and degas. 
       Sample Solution Preparation 
       [0081]    Weigh 20 intact capsules. Empty the capsules as completely as possible into a suitable container. Clean and weigh the empty capsule shells and determine the average capsule filled weight. Mix thoroughly the combined contents of the capsules. 
         [0082]    Weigh accurately amount of powder equivalent to 600 mg Gabapentin into a 50 ml volumetric flask. Add about 30 ml of mobile phase and sonicate for 10 minutes with intermittent shaking to disperse the powder. Shake for 30 minutes. Dilute to volume with mobile phase and mix well. Filter the solution. 
       Standard Solution Preparation 
       [0083]    Stock Standard Solution 
         [0084]    Weigh accurately about 25 mg Gabapentin R.S. and transfer to 50 ml volumetric flask. Add to it about 25 ml mobile phase. Sonicate to dissolve, make up the volume with mobile phase. 
         [0085]    Working Standard Solution 
         [0086]    Pipette out 6 ml of the solution from Standard Stock Solution into 50 ml volumetric Flask. Dilute to volume with mobile phase and mix well. 
       Resolution Solution Preparation 
       [0087]    Resolution stock solution (C.A.M) 
         [0088]    Weigh accurately about 12.5 mg of C.A.M., dissolved and dilute to 25 ml with methanol 
         [0089]    Note: Store under refrigeration for future use. The solution may be used as long as a peak due to C.A.M. is clearly visible in the chromatogram. 
       Resolution Working Solution 
       [0090]    Pipette out 6 ml of Standard Stock Solution and 6 ml of C.A.M. Stock Solution and dilute to 50 ml with mobile phase. 
       Lactam Marker Solution Preparation 
       [0091]    Lactam stock solution 
         [0092]    Weigh accurately about 12.5 mg lactam, dissolve and dilute to 25 ml with methanol. 
         [0093]    Note: Store under refrigeration for future use. The solution nay be used as long as the lactam peak is clearly seen. 
       Lactam Working Solution 
       [0094]    Pipette 6 ml of Lactam Stock solution and dilute to 50 ml with mobile phase. 
       Preparation of Methyl Parabens Marker Solution 
       [0095]    Weigh accurately about 25 mg of methyl parabens and dissolve and dilute to 50 ml with mobile phase. Pipette 5 ml of solution into a 50 ml volumetric flask and make up to volume with mobile phase. Further pipette 5 ml and dilute to 50 ml with mobile phase. 
       System Suitability 
       [0096]    System suitability test solution: Inject 50 μl of Resolution Solution into the equilibrated chromatograph. Calculate the system suitability requirements. Gabapentin peak has retention time of about 6 minutes. C.A.M. has retention time of about 10 minutes 
         [0097]    The resolution between Gabapentin and C. A. M. peaks is NLT 4.5 
         [0098]    The tailing factor (T), determined from the Gabapentin peak is NMT 2.0%. Perform 6 replicate injections of 50 μl of Working Standard Solution. The System precision is acceptable if the RSD of 6 replicate standard injections is NMT 5.0% 
       Procedure 
       [0099]    Separately inject 50 μl of the mobile phase, Standard Solution, lactam marker solution, Methyl Parabens marker solution and Test Solutions into the Chromatograph. Measure the responses of the major peaks. 
         [0100]    Calculate the content of impurity lactam: single largest individual/unidentified impurity/degradant and total impurities/degradant. 
         [0101]    Note: Identify the peak due to methyl parabens based upon the retention time in the chromatogram of the Methtyl Parabens marker solution. Disregard any peak occurring in the test solution at the same RRT as the Methyl Parabens peak. 
       Calculations 
       [0102]    A. Impurity 1: lactam {cyclohexanespiro (4,5) decane-2,3-butyrolactam}
       Note:   Identify the lactam peak based on the retention time in the chromatograms of the Lactam Maker Solution injection.   Resolve Response Factor for lactam (RRF)=21       
 
         [0000]    
       
         
           
             
               % 
                
               
                   
               
                
               Lactam 
             
             = 
             
               
                 
                   A 
                   T 
                 
                 
                   A 
                   S 
                 
               
               × 
               
                 1 
                 21 
               
               × 
               
                 Ws 
                 50 
               
               × 
               
                 6 
                 50 
               
               × 
               
                 P 
                 100 
               
               × 
               
                 50 
                 WT 
               
               × 
               
                 
                   Average 
                    
                   
                       
                   
                    
                   Filled 
                    
                   
                       
                   
                    
                   
                     Wt 
                     . 
                   
                 
                 
                   Label 
                    
                   
                       
                   
                    
                   Claim 
                 
               
               × 
               100 
             
           
         
       
     
       Where, 
       [0000]    
       
         
           
             AT=Peak area of lactam in Test Solution 
             AS=Peak area of Gabapentin in Standard Solution 
             P=Potency of Gabapentin W.S. 
             WS=Weight of Gabapentin W.S. in mg 
             WT=Weight of Test sample in mg. 
           
         
       
     
         [0111]    B. Single Largest Individual Unidentified Impurities/Degradant
       Determine the peak areas for individual impurities/degradant. For the largest peak areas observed other than those of diluent, lactam and Gabapentin peaks       
 
         [0000]    
       
         
           
             % 
              
             
                 
             
              
             Single 
              
             
                 
             
              
             largest 
              
             
                 
             
              
             individual 
              
             
                 
             
              
             
               impurities 
               / 
               degradants 
             
           
         
       
       
         
           
             
               
                 AT 
                 AS 
               
               × 
               
                 Ws 
                 50 
               
               × 
               
                 6 
                 50 
               
               × 
               
                 P 
                 100 
               
               × 
               
                 50 
                 WT 
               
               × 
               
                 
                   Average 
                    
                   
                       
                   
                    
                   Filled 
                    
                   
                       
                   
                    
                   
                     Wt 
                     . 
                   
                 
                 
                   Label 
                    
                   
                       
                   
                    
                   Claim 
                 
               
               × 
               100 
             
              
             
                 
             
           
         
       
     
       Where, 
       [0000]    
       
         
           
             AT=Peak area of any impurity in Test Solution 
             AS=Peak area of Gabapentin in Standard Solution 
             P=Potency of Gabapentin W.S. 
             WS=Weight of Gabapentin W.S. in mg. 
             WT=Weight of Test sample in mg. 
           
         
       
     
         [0118]    C. Total other impurities/degradants: 
         [0119]    Sum the peak areas of all unidentified impurities. 
         [0000]    
       
         
           
             
               % 
                
               
                   
               
                
               Total 
                
               
                   
               
                
               other 
                
               
                   
               
                
               
                 impurities 
                 / 
                 degradants 
               
             
             = 
             
               
                 
                   ∑ 
                   AT 
                 
                 AS 
               
               × 
               
                 Ws 
                 50 
               
               × 
               
                 6 
                 50 
               
               × 
               
                 P 
                 100 
               
               × 
               
                 50 
                 WT 
               
               × 
               
                 
                   Average 
                    
                   
                       
                   
                    
                   Filled 
                    
                   
                       
                   
                    
                   
                     Wt 
                     . 
                   
                 
                 
                   Label 
                    
                   
                       
                   
                    
                   Claim 
                 
               
               × 
               100 
             
           
         
       
     
       Where, 
       [0000]    
       
         
           
             ΣAT=Peak area of any impurity in Test Solution 
             AS=Peak area of Gabapentin in Standard Solution 
             P=Potency of Gabapentin W.S. 
             WS=Weight of Gabapentin W.S. in mg. 
             WT=Weight of Test sample in mg. 
           
         
       
     
         [0125]    D. % Total Impurities/degradant: 
         [0126]    =% lactam+% total other impurities/degradants 
       Medicinal Products 
       [0127]    Exemplary medicinal products containing gabapentin are disclosed in Table 1. Table 1 relates to gabapentin formulations containing active doses at 100, 200 and 400 mg. In hard gelatine capsules. Excipients include microcrystalline cellulose as the sole diluent and magnesium stearate as a lubricant. Table 1 additionally sets out capsule shell constituents and also constituents of the printing ink. 
         [0128]    Stability data for the formulations of Table 1 at a range of temperatures (20° C. to 40° C.) and durations is provided in Tables 4 through 18. 
       Composition 
       [0129]    Composition of Proprietary Medicinal Product 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Composition of the proprietary medical product 
               
             
          
           
               
                   
                 mg/unit 
                   
                 Reference 
               
             
          
           
               
                 Name of Ingredients 
                 100 mg 
                 300 mg 
                 400 mg 
                 Function 
                 to standards 
               
               
                   
               
             
          
           
               
                 Active Ingredient 
                   
                   
                   
                   
                   
               
               
                 Gabapentin 
                 100.00 
                 300.00 
                 400.00 
                 Active 
                 HSE 
               
               
                 Other Ingredients 
               
               
                 Cellulose, microcrystalline (Avicel 
                 11.75 
                 35.25 
                 47.00 
                 Diluent 
                 Ph. Eur. 
               
               
                 PH 200) 
               
               
                 Magnesium stearate 
                 1.50 
                 4.50 
                 6.00 
                 Lubricant 
                 Ph. Eur. 
               
               
                 Total fill weight 
                 113.25 
                 339.75 
                 453.00 
               
               
                 Empty Hard Gelatin Capsule 
                 Size ‘3’ 
                 Size ‘1’ 
                 Size ‘0’ 
                 Capsule shell 
                 HSE 
               
               
                 Shell 
               
               
                 Methyl parahydroxybenzoate 
                 0.400 
                 0.620 
                 0.784 
                   
                 Ph. Eur. 
               
               
                 (E218) 
               
               
                 Propyl parahydroxybenzoate 
                 0.100 
                 0.155 
                 0.196 
                   
                 Ph. Eur. 
               
               
                 (E216) 
               
               
                 Sodium laurilsulfate 
                 0.040 
                 0.062 
                 0.078 
                   
                 Ph. Eur. 
               
               
                 Titanium oxide (E171) 
                 1.083 
                 0.839 
                 1.304 
                   
                 Ph. Eur. 
               
               
                 Yellow iron oxide (E172) 
                 — 
                 0.465 
                 0.784 
                   
                 HSE 
               
               
                 Red iron oxide (E172) 
                 — 
                 — 
                 0.078 
                   
                 HSE 
               
               
                 Purified water 
                 7.250 
                 11.238 
                 14.210 
                   
                 Ph. Eur. 
               
               
                 Gelatin 
                 41.127 
                 64.121 
                 80.554 
                   
                 Ph. Eur. 
               
               
                 Constituents of the printing ink 
               
               
                 Ethanol anhydrous 
                   
                   
                   
                   
                 Ph. Eur. 
               
               
                 Isopropyl alcohol 
                   
                   
                   
                   
                 Ph. Eur. 
               
               
                 Shellac 
                   
                   
                   
                   
                 Ph. Eur. 
               
               
                 Activated charcoal 
                   
                   
                   
                   
                 Ph. Eur. 
               
               
                   
               
             
          
         
       
     
       Stability 
       [0130]    Stability Tests on the Finished Product 
         [0131]    Quality Specification for the proposed shelf-life 
         [0132]    The Stability specification for Gabapentin Capsules 100 mg, 300 mg and 400 mg is presented in Table 2 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Stability Specification and routine tests for Gabapentin Capsules 
               
             
          
           
               
                   
                 Specification 
               
             
          
           
               
                 Test 
                 100 mg capsule 
                 300 mg capsule 
                 400 mg capsule 
               
               
                   
               
               
                 Appearance (Visual)* 
                 White/white Size ‘3’ hard 
                 Yellow/yellow Size ‘1’ hard 
                 Orange/orange Size ‘0’ hard 
               
               
                   
                 gelatin capsules containing 
                 gelatin capsules containing 
                 gelatin capsules containing 
               
               
                   
                 white to off white powder 
                 white to off white powder 
                 white to off white powder 
               
               
                   
                 printed ‘GAB 100’ and twin 
                 printed with ‘GAB 300’ and 
                 printed with ‘GAB 400’ and 
               
               
                   
                 triangle logo in black ink 
                 twin triangle logo in black ink 
                 twin triangle logo in black ink 
               
               
                 Average capsule weight 
                 163.2 mg ± 5% 
                 415.7 mg ± 5% 
                 548.0 mg ± 5% 
               
               
                 Average filled weight 
                 113.2 mg ± 5% 
                 339.7 mg ± 5% 
                 453.0 mg ± 5% 
               
               
                 Uniformity of filled 
                 ±10% of average filled 
                 ±7.5% of average filled 
                 ±7.5% of average filled 
               
               
                 weight 
                 weight 
                 weight 
                 weight 
               
               
                 Disintegration (Ph. Eur.) 
                 NMT 15 minutes 
                 NMT 15 minutes 
                 NMT 15 minutes 
               
               
                 Water content (by KF) 
                 NMT 3% 
                 NMT 3% 
                 NMT 3% 
               
               
                 Related Substances 
               
               
                 (TA 02) 
               
               
                 Lactam 
                 NMT 0.3% 
                 NMT 0.3% 
                 NMT 0.3% 
               
               
                 Any other impurities 
                 NMT 0.1% 
                 NMT 0.1% 
                 NMT 0.1% 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 NMT 1.0% 
                 NMT 1.0% 
               
               
                 (including Lactam) 
               
               
                 Dissolution (TA 03) 
                 NLT 80% in 20 minutes 
                 NLT 80% in 20 minutes 
                 NLT 80% in 20 minutes 
               
               
                 Assay: Content of 
                 95.0-105.0% 
                 95.0-105.0% 
                 95.0-105.0% 
               
               
                 Gabapentin (TA 05) 
               
               
                 Microbial Limits (1)   
                 NMT 1000 bacteria per gm 
                 NMT 1000 bacteria per gm 
                 NMT 1000 bacteria per gm 
               
               
                   
                 NMT 100 fungi per gm. 
                 NMT 100 fungi per gm. 
                 NMT 100 fungi per gm. 
               
               
                   
                   E. coli  - absent 
                   E. coli  - absent 
                   E. coli  - absent 
               
               
                   
               
               
                   (1) To be tested on initial, 6, 24 and 36 months. 
               
             
          
         
       
     
       Batches Tested and Packaging 
       [0133]      
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Details of batches put on stability 
               
             
          
           
               
                   
                   
                 Drug 
                 Batch 
                   
                   
               
               
                 Capsule 
                   
                 substance 
                 size 
                   
                 Date on 
               
               
                 strength 
                 Batch 
                 batch 
                 (Cap- 
                 Date of 
                 stability 
               
               
                 (mg) 
                 number 
                 number 
                 sules) 
                 manufacture 
                 test 
               
               
                   
               
               
                 100 mg 
                 GBC-I/100 
                  28800398 
                 100,000 
                 April 1999 
                 July 1999 
               
               
                   
                   
                 288010498 
               
               
                 100 mg 
                 GBC-II/100 
                 288010498 
                 100,000 
                 April 1999 
                 July 1999 
               
               
                   
                   
                 288070399 
               
               
                 300 mg 
                 GBC-I/300 
                  28800398 
                 100,000 
                 March 1999 
                 May 1999 
               
               
                   
                   
                 288010498 
               
               
                 300 mg 
                 GBC-II/300 
                 288010498 
                 100,000 
                 April 1999 
                 May 1999 
               
               
                   
                   
                 288070399 
               
               
                 400 mg 
                 GBC-I/400 
                  28800398 
                 110,000 
                 March 1999 
                 May 1999 
               
               
                   
                   
                 288010498 
               
               
                 400 mg 
                 GBC-II/400 
                 288010498 
                 110,000 
                 April 1999 
                 May 1999 
               
               
                   
                   
                 288070399 
               
               
                   
               
             
          
         
       
     
         [0134]    Active drug substance used for the manufacture of the above batches was supplied from Teva. All batches were manufactured at Nicholas Piramal (Pithampur) Limited, India. 
         [0135]    The above stability batches were packed into white opaque PVC/PVdC/Aluminium blister strips. These blister strips were cartooned prior to being placed on test. 
       Storage Conditions 
     Real Time Studies 
       [0136]    Stability samples were stored at 25° C.±2° C./60%±5% RH and 30° C.±2° C./60%±5% RH and were tested at initial, 3, 6, 12, 18 and 24 and 36 month time points and 3, 6, 12, 18 and 24 month time points respectively. 
       Studies Under Other Conditions (Accelerated Conditions) 
       [0137]    Stability samples were stored at 40° C.±2° C./75%±5% RH and were tested at initial, 1 month, 2 months, 3 months and 6 months time points. 
       Evaluation Test Procedures 
       [0138]    The analytical methods for all the tests used in the stability studies are the same as proposed for routine batch analysis and are known to persons skilled in the art. The methodology for, related substances and assay has been validated and are suitable for stability purposes. 
         [0139]    The assay and related substances methods used throughout the stability studies are stability indicating. 
       Results of Tests 
     Results of Physical Testing 
       [0140]    The stability data is for 6 months for all strengths at accelerated conditions and for 36 months at 25° C.±2° C./60%±5% RH and 24 months at 30° C.±2° C./60%±5% RH. The results of physical testing of the stability batches packed in PVC/PVdC/Aluminium blister packs is shown in Tables 4 to 19. 
         [0141]    Throughout the period of study under all the conditions 25° C.±2° C./60%5% RH, 30° C.±2° C./60%±5% RH and 40° C.±2° C./75%±5% RH, no significant changes were noted in the appearance or disintegration time of any of the samples on test. It is noted none of the stability batches have the markings proposed for marketing, however this does not affect the stability profile. 
         [0142]    The percentage water content by KF had shown an increase after one month study in the test samples for 300 and 400 mg strengths. 
         [0143]    However, at the end of the second month, once again a similar trend was observed and investigation was initiated as per the SOP for out of specification. The result of the investigation indicated that the test was performed after 6-7 hours of removal of the powder blend from the capsule. The exposure to atmosphere could have resulted in higher values. The statement to the effect that KF should be done on fresh samples only has been included in the method of analysis. 
       Results of Chemical Testing 
     Related Substances/Impurities 
       [0144]    The amount of all the secondary peaks obtained was calculated with respect to Gabapentin diluted standard. In the determination of the amount of known impurity i.e. lactam, the higher response of this impurity (RRF=21 relative to gabapentin) was accounted for in the calculation. From Tables 4 to 19, it may be noted that the value for lactam is well below 0.2% up to 3 months interval for all the strengths. However, at the sixth month interval, the values obtained were slightly above 0.2%. 
         [0145]    One unknown impurity at a RRT of about 6.0 was noted under accelerated conditions (40° C.±2° C./75%±5% RH) at the end of one month. Investigation was taken up with respect to the identification and characterisation of this impurity and it was found to be due to the preservative, methyl parabens, present in the capsule shells. The methodology was therefore revised to include preparation of a methyl parabens marker solution and to disregard any peaks occurring in the test samples at the same retention time as the marker. 
         [0146]    Total impurities were found to be within the shelf life limits proposed. 
       Dissolution 
       [0147]    No significant changes were observed in the dissolution results of any of the samples under test. 
       Assay 
       [0148]    Up to 36 months data at 25° C.2±° C./60%±5% RH, 24 months data at 30° C.±2° C./60%±5% RH and 6 months at 40° C.±2° C./75%±5% RH are available for all strengths of capsules. The data are within specification limits for all the batches. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-I/100) stored at 25° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                 3 
                 6 
                 9 
                 12 
                 18 
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 White/white, Size ‘3’ 
                 White/white, Size ‘3’ 
                 NT 
                 NT 
                 As 
                 As 
                 As 
                 As 
                 As 
                 As initial 
               
               
                   
                 hard gelatin capsules 
                 hard gelatin capsules 
                   
                   
                 initial 
                 initial 
                 initial 
                 initial 
                 initial 
               
               
                   
                 containing white to off 
                 containing white to off 
               
               
                   
                 white powder, printed 
                 white powder, printed 
               
               
                   
                 with logo in black ink. 
                 with logo in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 8-9 
                 NT 
                 NT 
                 8-9 
                 8-9 
                 6-7 
                 7-8 
                 6-7 
                 6-7 
               
               
                 Water content (%) 
                 NMT 3% 
                  1.65 
                 NT 
                 NT 
                 1.75 
                 1.82 
                 1.75 
                 1.70 
                 1.51 
                 1.56 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.040 
                 0.069 
                 0.136 
                 0.146 
                 0.208 
                 0.157 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 NT 
                 NT 
                 0.002 
                 0.003 
                 0.004 
                 0.004 
                 0.007 
                 0.007 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.001 
                 NT 
                 NT 
                 0.085 
                 0.120 
                 0.256 
                 0.277 
                 0.410 
                 0.269 
               
               
                 Dissolution 
                 NLT 80% dissolved in 
                 99.80 
                 NT 
                 NT 
                 100.3 
                 99.37 
                 98.54 
                 97.95 
                 100.00 
                 98.99 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 98.20 
                 NT 
                 NT 
                 98.53 
                 98.78 
                 98.79 
                 98.36 
                 98.56 
                 98.62 
               
               
                 Microbial Limits 
                 NMT 1000 bacteria per 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 gm 
               
               
                   
                 NMT 100 fungi per gm. 
                   E. coli  - absent 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-I/100) stored at 30° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                 1 
                   
                 2 
                 3 
                 6 
                 9 
                 12 
                 18 
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 White/white, Size ‘3’ 
                 White/white, Size ‘3’ 
                 NT 
                 NT 
                 As 
                 As 
                 As 
                 As 
                 As 
                 As initial 
               
               
                   
                 hard gelatin capsules 
                 hard gelatin capsules 
                   
                   
                 initial 
                 initial 
                 initial 
                 initial 
                 initial 
               
               
                   
                 containing white to off 
                 containing white to off 
               
               
                   
                 white powder, printed 
                 white powder, printed 
               
               
                   
                 with logo in black ink. 
                 with logo in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 8-9 
                 NT 
                 NT 
                 6-7 
                 7-8 
                 7-8 
                 8-9 
                 8-9 
                 8-9 
               
               
                 Water content (%) 
                 NMT 3% 
                  1.65 
                 NT 
                 NT 
                 1.70 
                 1.80 
                 1.78 
                 1.69 
                 1.69 
                 1.49 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.062 
                 0.096 
                 0.136 
                 0.223 
                 0.260 
                 0.267 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 NT 
                 NT 
                 0.002 
                 0.003 
                 0.004 
                 0.005 
                 0.008 
                 0.009 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.001 
                 NT 
                 NT 
                 0.099 
                 0.250 
                 0.252 
                 0.415 
                 0.465 
                 0.363 
               
               
                 Dissolution 
                 NLT 80% dissolved in 
                 99.80 
                 NT 
                 NT 
                 87.22 
                 99.29 
                 98.92 
                 99.70 
                 99.80 
                 99.02 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 98.20 
                 NT 
                 NT 
                 98.32 
                 98.41 
                 98.93 
                 98.92 
                 98.38 
                 98.45 
               
               
                 Microbial Limits 
                 NMT 1000 bacteria per 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 gm 
               
               
                   
                 NMT 100 fungi per gm. 
                   E. coli  - absent 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-I/100) stored at 40° C. ± 2° C./75% ± 5% RH 
               
             
          
           
               
                 Test Performed 
                 Limits 
                 Initial 
                 1 Month 
                 2 Month 
                 3 Month 
                 6 Month 
               
               
                   
               
               
                 Appearance 
                 White/white, Size ‘3’ 
                 White/white, Size ‘3’ 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 hard gelatin capsules 
                 hard gelatin capsules 
               
               
                   
                 containing white to off 
                 containing white to off 
               
               
                   
                 white powder, printed 
                 white powder, printed 
               
               
                   
                 with logo in black ink. 
                 with logo in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 8-9 
                 8-9 
                 8-9 
                 8-9 
                 7-8 
               
               
                 Water content (%) 
                 NMT 3% 
                  1.65 
                 1.65 
                 1.82 
                 1.84 
                 1.82 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 0.064 
                 0.145 
                 0.144 
                 0.206 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 0.017 
                 0.046 
                 0.061 
                 0.079 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.001 
                 0.160 
                 0.334 
                 0.375 
                 0.585 
               
               
                 Dissolution 
                 NLT 80% dissolved in 
                 99.80 
                 98.96 
                 97.66 
                 102.6 
                 99.53 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 98.20 
                 98.46 
                 98.32 
                 98.82 
                 98.94 
               
               
                 Microbial Limits 
                 NMT 1000 bacteria per 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 gm 
               
               
                   
                 NMT 100 fungi per gm. 
                   E. coli  - absent 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-II/100) stored at 25° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                 3 
                 6 
                 9 
                 12 
                 18 
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 White/white, Size ‘3’ 
                 White/white, Size ‘3’ 
                 NT 
                 NT 
                 As 
                 As 
                 As 
                 As 
                 As 
                 As initial 
               
               
                   
                 hard gelatin capsules 
                 hard gelatin capsules 
                   
                   
                 initial 
                 initial 
                 initial 
                 initial 
                 initial 
               
               
                   
                 containing white to off 
                 containing white to off 
               
               
                   
                 white powder, printed 
                 white powder, printed 
               
               
                   
                 with logo in black ink. 
                 with logo in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 6-7 
                 NT 
                 NT 
                 6-7 
                 8-9 
                 6-7 
                 8-9 
                 7-8 
                 8-9 
               
               
                 Water content (%) 
                 NMT 3% 
                  1.68 
                 NT 
                 NT 
                 1.85 
                 1.71 
                 1.70 
                 1.65 
                 1.53 
                 1.58 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.021 
                 0.046 
                 0.097 
                 0.138 
                 0.168 
                 0.155 
               
               
                 Any other individual 
                 NMT 0.1% 
                  &lt;0.001 
                 NT 
                 NT 
                 0.002 
                 0.003 
                 0.004 
                 0.004 
                 0.008 
                 0.007 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                  &lt;0.021 
                 NT 
                 NT 
                 0.045 
                 0.113 
                 0.214 
                 0.302 
                 0.277 
                 0.278 
               
               
                 Dissolution 
                 NLT 80% dissolved in 
                 102.70 
                 NT 
                 NT 
                 106.45 
                 98.85 
                 99.86 
                 100.37 
                 100.03 
                 98.94 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                  98.10 
                 NT 
                 NT 
                 99.58 
                 98.91 
                 98.68 
                 98.65 
                 98.67 
                 98.52 
               
               
                 Microbial Limits 
                 NMT 1000 bacteria per 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 gm 
               
               
                   
                 NMT 100 fungi per gm. 
                   E. coli  - absent 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-II/100) stored at 30° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                 3 
                 6 
                 9 
                 12 
                 18 
                 24 
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
               
               
                   
               
               
                 Appearance 
                 White/white, 
                 White/white, 
                 NT 
                 NT 
                 As 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 Size ‘3’ hard 
                 Size ‘3’ hard 
                   
                   
                 initial 
               
               
                   
                 gelatin capsules 
                 gelatin capsules 
               
               
                   
                 containing white 
                 containing white 
               
               
                   
                 to off white 
                 to off white 
               
               
                   
                 powder, printed 
                 powder, printed 
               
               
                   
                 with logo 
                 with logo 
               
               
                   
                 in black ink. 
                 in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 6-7 
                 NT 
                 NT 
                 7-8 
                 6-7 
                 6-7 
                 8-9 
                 8-9 
                 8-9 
               
               
                 Water content (%) 
                 NMT 3% 
                 1.68 
                 NT 
                 NT 
                 1.81 
                 1.78 
                 1.74 
                 1.70 
                 1.57 
                 1.67 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.030 
                 0.073 
                 0.098 
                 0.208 
                 0.218 
                 0.268 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 NT 
                 NT 
                 0.001 
                 0.003 
                 0.004 
                 0.005 
                 0.007 
                 0.010 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.021 
                 NT 
                 NT 
                 0.037 
                 0.094 
                 0.213 
                 0.381 
                 0.367 
                 0.344 
               
               
                 Dissolution 
                 NLT 80% dissolved 
                 102.70 
                 NT 
                 NT 
                 109.37 
                 99.01 
                 101.90 
                 99.59 
                 99.79 
                 99.22 
               
               
                   
                 in 20 minutes 
               
               
                 Assay 
                 95-105% 
                 98.10 
                 NT 
                 NT 
                 98.93 
                 98.28 
                 98.57 
                 98.53 
                 98.94 
                 98.87 
               
               
                 Microbial Limits 
                 NMT 1000 bacteria 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 per gm 
               
               
                   
                 NMT 100 fungi 
                   E. coli  - absent 
               
               
                   
                 per gm. 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-II/100) stored at 40° C. ± 2° C./75% ± 5% RH 
               
             
          
           
               
                 Test Performed 
                 Limits 
                 Initial 
                 1 Month 
                 2 Month 
                 3 Month 
                 6 Month 
               
               
                   
               
               
                 Appearance 
                 White/white, Size ‘3’ 
                 White/white, Size ‘3’ 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 hard gelatin capsules 
                 hard gelatin capsules 
               
               
                   
                 containing white to off 
                 containing white to off 
               
               
                   
                 white powder, printed 
                 white powder, printed 
               
               
                   
                 with logo in black ink. 
                 with logo in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 6-7 
                 7-8 
                 6-7 
                 7-8 
                 7-8 
               
               
                 Water content (%) 
                 NMT 3% 
                 1.68 
                 1.66 
                 1.87 
                 1.80 
                 1.82 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 0.039 
                 0.117 
                 0.103 
                 0.184 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 0.017 
                 0.043 
                 0.054 
                 0.073 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.021 
                 0.221 
                 0.239 
                 0.384 
                 0.579 
               
               
                 Dissolution 
                 NLT 80% dissolved in 
                 102.70 
                 103.84 
                 103.8 
                 108.80 
                 98.80 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 98.10 
                 100.02 
                 99.22 
                 98.84 
                 98.73 
               
               
                 Microbial Limits 
                 NMT 1000 bacteria per 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 gm 
               
               
                   
                 NMT 100 fungi per gm. 
                   E. coli  - absent 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-I/300) stored at 25° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                 3 
                 6 
                 9 
                 12 
                 18 
                 24 
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
                 Month 
               
               
                   
               
               
                 Appearance 
                 Yellow/yellow, 
                 Yellow/yellow, 
                 NT 
                 NT 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 Size ‘1’ hard 
                 Size ‘1’ hard 
               
               
                   
                 gelatin capsules 
                 gelatin capsules 
               
               
                   
                 containing white 
                 containing white 
               
               
                   
                 to off white 
                 to off white 
               
               
                   
                 powder, printed 
                 powder, printed 
               
               
                   
                 with logo in 
                 with logo in 
               
               
                   
                 black ink. 
                 black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 9-10 
                 NT 
                 NT 
                 9-10 
                 8-9 
                 7-8 
                 7-8 
                 6-7 
                 7-8 
               
               
                 Water content (%) 
                 NMT 3% 
                 1.19 
                 NT 
                 NT 
                 1.22 
                 1.17 
                 1.12 
                 1.12 
                 1.04 
                 0.90 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.016 
                 0.032 
                 0.050 
                 0.061 
                 0.099 
                 0.134 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 NT 
                 NT 
                 &lt;0.001 
                 &lt;0.001 
                 0.001 
                 0.001 
                 0.001 
                 0.002 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 0.011 
                 NT 
                 NT 
                 &lt;0.019 
                 &lt;0.088 
                 0.109 
                 0.154 
                 0.293 
                 0.279 
               
               
                 Dissolution 
                 NLT 80% 
                 102.80 
                 NT 
                 NT 
                 104.62 
                 99.63 
                 99.01 
                 96.14 
                 99.59 
                 98.72 
               
               
                   
                 dissolved in 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 100.40 
                 NT 
                 NT 
                 100.54 
                 98.56 
                 98.60 
                 99.10 
                 99.01 
                 101.06 
               
               
                 Microbial Limits 
                 NMT 1000 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 bacteria per gm 
               
               
                   
                 NMT 100 fungi 
                   E. coli  - absent 
               
               
                   
                 per gm. 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-I/300) stored at 30° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                   
                   
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 3 Month 
                 6 Month 
                 9 Month 
                 12 Month 
                 18 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 Yellow/yellow, 
                 Yellow/yellow, 
                 NT 
                 NT 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 Size ‘1’ hard 
                 Size ‘1’ hard 
               
               
                   
                 gelatin capsules 
                 gelatin capsules 
               
               
                   
                 containing white 
                 containing white 
               
               
                   
                 to off white 
                 to off white 
               
               
                   
                 powder, printed 
                 powder, printed 
               
               
                   
                 with logo 
                 with logo 
               
               
                   
                 in black ink. 
                 in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 9-10 
                 NT 
                 NT 
                 8-9 
                 9-10 
                 8-9 
                 8-9 
                 8-9 
                 6-7 
               
               
                 Water content (%) 
                 NMT 3% 
                 1.19 
                 NT 
                 NT 
                 1.20 
                 1.13 
                 1.14 
                 1.12 
                 1.02 
                 0.89 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.017 
                 0.043 
                 0.067 
                 0.122 
                 0.176 
                 0.209 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 NT 
                 NT 
                 &lt;0.001 
                 &lt;0.001 
                 0.001 
                 0.006 
                 0.002 
                 0.003 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 0.011 
                 NT 
                 NT 
                 &lt;0.079 
                 &lt;0.093 
                 0.394 
                 0.328 
                 0.465 
                 0.471 
               
               
                 Dissolution 
                 NLT 80% 
                 102.80 
                 NT 
                 NT 
                 101.6 
                 99.27 
                 101.70 
                 98.14 
                 98.37 
                 99.59 
               
               
                   
                 dissolved in 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 100.40 
                 NT 
                 NT 
                 100.26 
                 99.01 
                 99.01 
                 99.10 
                 98.92 
                 100.54 
               
               
                 Microbial Limits 
                 NMT 1000 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 bacteria per gm 
               
               
                   
                 NMT 100 fungi 
                   E. coli  - absent 
               
               
                   
                 per gm. 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-II/300) stored at 30° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                   
                   
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 3 Month 
                 6 Month 
                 9 Month 
                 12 Month 
                 18 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 Yellow/yellow, 
                 Yellow/yellow, 
                 NT 
                 NT 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 Size ‘1’ hard 
                 Size ‘1’ hard 
               
               
                   
                 gelatin capsules 
                 gelatin capsules 
               
               
                   
                 containing white 
                 containing white 
               
               
                   
                 to off white 
                 to off white 
               
               
                   
                 powder, printed 
                 powder, printed 
               
               
                   
                 with logo 
                 with logo 
               
               
                   
                 in black ink. 
                 in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 6-7 
                 NT 
                 NT 
                 8-9 
                 7-8 
                 8-9 
                 7-8 
                 7-8 
                 7-8 
               
               
                 Water content (%) 
                 NMT 3% 
                 0.54 
                 NT 
                 NT 
                 1.21 
                 1.16 
                 1.12 
                 1.15 
                 1.00 
                 0.96 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.016 
                 0.037 
                 0.055 
                 0.106 
                 0.144 
                 0.189 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 NT 
                 NT 
                 &lt;0.001 
                 0.002 
                 0.002 
                 0.003 
                 0.002 
                 0.003 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.012 
                 NT 
                 NT 
                 &lt;0.177 
                 0.234 
                 0.219 
                 0.209 
                 0.317 
                 0.459 
               
               
                 Dissolution 
                 NLT 80% 
                 98.06 
                 NT 
                 NT 
                 100.86 
                 95.70 
                 101.38 
                 102.60 
                 102.14 
                 101.92 
               
               
                   
                 dissolved in 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 99.60 
                 NT 
                 NT 
                 98.05 
                 98.04 
                 98.90 
                 99.04 
                 98.71 
                 98.37 
               
               
                 Microbial Limits 
                 NMT 1000 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 bacteria per gm 
               
               
                   
                 NMT 100 fungi 
                   E. coli  - absent 
               
               
                   
                 per gm. 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-II/300) stored at 25° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                   
                   
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 3 Month 
                 6 Month 
                 9 Month 
                 12 Month 
                 18 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 Yellow/yellow, 
                 Yellow/yellow, 
                 NT 
                 NT 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 Size ‘1’ hard 
                 Size ‘1’ hard 
               
               
                   
                 gelatin capsules 
                 gelatin capsules 
               
               
                   
                 containing white 
                 containing white 
               
               
                   
                 to off white 
                 to off white 
               
               
                   
                 powder, printed 
                 powder, printed 
               
               
                   
                 with logo 
                 with logo 
               
               
                   
                 in black ink. 
                 in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 6-7 
                 NT 
                 NT 
                 7-8 
                 7-8 
                 7-8 
                 6-7 
                 7-8 
                 6-7 
               
               
                 Water content (%) 
                 NMT 3% 
                 0.54 
                 NT 
                 NT 
                 1.27 
                 1.20 
                 1.14 
                 1.13 
                 1.00 
                 0.92 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.011 
                 0.028 
                 0.042 
                 0.060 
                 0.066 
                 0.111 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 NT 
                 NT 
                 &lt;0.001 
                 0.001 
                 0.002 
                 0.002 
                 0.002 
                 0.002 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.012 
                 NT 
                 NT 
                 &lt;0.126 
                 0.158 
                 0.108 
                 0.233 
                 0.260 
                 0.263 
               
               
                 Dissolution 
                 NLT 80% 
                 98.06 
                 NT 
                 NT 
                 101.49 
                 97.74 
                 101.66 
                 101.32 
                 99.88 
                 100.60 
               
               
                   
                 dissolved in 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 99.60 
                 NT 
                 NT 
                 98.66 
                 97.87 
                 97.68 
                 98.20 
                 98.65 
                 99.75 
               
               
                 Microbial Limits 
                 NMT 1000 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 bacteria per gm 
               
               
                   
                 NMT 100 fungi 
                   E. coli  - absent 
               
               
                   
                 per gm. 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-I/400) stored at 25° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                   
                   
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 3 Month 
                 6 Month 
                 9 Month 
                 12 Month 
                 18 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 Orange/orange, 
                 Orange/orange, 
                 NT 
                 NT 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 Size ‘1’ hard 
                 Size ‘1’ hard 
               
               
                   
                 gelatin capsules 
                 gelatin capsules 
               
               
                   
                 containing white 
                 containing white 
               
               
                   
                 to off white 
                 to off white 
               
               
                   
                 powder, printed 
                 powder, printed 
               
               
                   
                 with logo 
                 with logo 
               
               
                   
                 in black ink. 
                 in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 6-7 
                 NT 
                 NT 
                 7-8 
                 6-7 
                 7-8 
                 7-8 
                 7-8 
                 6-7 
               
               
                 Water content (%) 
                 NMT 3% 
                 1.19 
                 NT 
                 NT 
                 1.20 
                 1.14 
                 1.20 
                 1.06 
                 1.06 
                 0.99 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.013 
                 0.025 
                 0.042 
                 0.058 
                 0.074 
                 0.104 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 NT 
                 NT 
                 &lt;0.001 
                 &lt;0.001 
                 0.001 
                 0.001 
                 0.001 
                 0.002 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.001 
                 NT 
                 NT 
                 &lt;0.099 
                 &lt;0.050 
                 0.187 
                 0.221 
                 0.212 
                 0.196 
               
               
                 Dissolution 
                 NLT 80% 
                 101.70 
                 NT 
                 NT 
                 99.25 
                 99.20 
                 100.37 
                 98.45 
                 99.64 
                 98.92 
               
               
                   
                 dissolved in 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 101.70 
                 NT 
                 NT 
                 98.30 
                 98.09 
                 98.12 
                 98.52 
                 98.13 
                 99.40 
               
               
                 Microbial Limits 
                 NMT 1000 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 bacteria per gm 
               
               
                   
                 NMT 100 fungi 
                   E. coli  - absent 
               
               
                   
                 per gm. 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 15 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-I/400) stored at 30° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                   
                   
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 3 Month 
                 6 Month 
                 9 Month 
                 12 Month 
                 18 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 Orange/orange, 
                 Orange/orange, 
                 NT 
                 NT 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 Size ‘1’ hard 
                 Size ‘1’ hard 
               
               
                   
                 gelatin capsules 
                 gelatin capsules 
               
               
                   
                 containing white 
                 containing white 
               
               
                   
                 to off white 
                 to off white 
               
               
                   
                 powder, printed 
                 powder, printed 
               
               
                   
                 with logo 
                 with logo 
               
               
                   
                 in black ink. 
                 in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 6-7 
                 NT 
                 NT 
                 6-7 
                 7-8 
                 6-7 
                 6-7 
                 7-8 
                 6-7 
               
               
                 Water content (%) 
                 NMT 3% 
                 1.19 
                 NT 
                 NT 
                 1.23 
                 1.18 
                 1.08 
                 1.19 
                 1.02 
                 1.00 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.016 
                 0.037 
                 0.05 
                 0.090 
                 0.125 
                 0.184 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 NT 
                 NT 
                 0.001 
                 &lt;0.001 
                 0.001 
                 0.002 
                 0.002 
                 0.003 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.001 
                 NT 
                 NT 
                 0.234 
                 &lt;0.174 
                 0.171 
                 0.243 
                 0.343 
                 0.410 
               
               
                 Dissolution 
                 NLT 80% 
                 101.70 
                 NT 
                 NT 
                 100.25 
                 99.20 
                 99.42 
                 97.33 
                 101.28 
                 98.21 
               
               
                   
                 dissolved in 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 101.70 
                 NT 
                 NT 
                 99.35 
                 98.09 
                 98.48 
                 98.14 
                 98.25 
                 97.42 
               
               
                 Microbial Limits 
                 NMT 1000 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 bacteria per gm 
               
               
                   
                 NMT 100 fungi 
                   E. coli  - absent 
               
               
                   
                 per gm. 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 16 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-I/400) stored at 40° C. ± 2° C./75% ± 5% RH 
               
             
          
           
               
                 Test Performed 
                 Limits 
                 Initial 
                 1 Month 
                 2 Month 
                 3 Month 
                 6 Month 
               
               
                   
               
               
                 Appearance 
                 Orange/orange, Size ‘0’ 
                 Orange/orange, Size ‘0’ 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 hard gelatin capsules 
                 hard gelatin capsules 
               
               
                   
                 containing white to off 
                 containing white to off 
               
               
                   
                 white powder, printed 
                 white powder, printed 
               
               
                   
                 with logo in black ink. 
                 with logo in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 6-7 
                 7-8 
                 7-8 
                 7-8 
                 7-8 
               
               
                 Water content (%) 
                 NMT 3% 
                 1.19 
                 1.50 
                 1.52 
                 1.58 
                 1.51 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 0.040 
                 0.075 
                 0.080 
                 0.185 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 0.005 
                 0.018 
                 0.014 
                 0.039 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.001 
                 0.045 
                 0.460 
                 0.314 
                 0.469 
               
               
                 Dissolution 
                 NLT 80% dissolved in 
                 101.70 
                 99.64 
                 101.54 
                 98.93 
                 91.59 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 101.70 
                 99.28 
                 98.52 
                 97.84 
                 98.23 
               
               
                 Microbial Limits 
                 NMT 1000 bacteria per 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 10 CFU 
               
               
                   
                 gm 
                   
                   
                   
                   
                 absent 
               
               
                   
                 NMT 100 fungi per gm. 
                   E. coli  - absent 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 17 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-II/400) stored at 25° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                   
                   
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 3 Month 
                 6 Month 
                 9 Month 
                 12 Month 
                 18 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 Orange/orange, 
                 Orange/orange, 
                 NT 
                 NT 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 Size ‘1’ hard 
                 Size ‘1’ hard 
               
               
                   
                 gelatin capsules 
                 gelatin capsules 
               
               
                   
                 containing white 
                 containing white 
               
               
                   
                 to off white 
                 to off white 
               
               
                   
                 powder, printed 
                 powder, printed 
               
               
                   
                 with logo 
                 with logo 
               
               
                   
                 in black ink. 
                 in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 10-11 
                 NT 
                 NT 
                 10-11 
                 10-11 
                 10-11 
                 10-11 
                 9-10 
                 9-10 
               
               
                 Water content (%) 
                 NMT 3% 
                 0.54 
                 NT 
                 NT 
                 1.14 
                 1.10 
                 1.05 
                 1.05 
                 1.00 
                 0.95 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.010 
                 0.028 
                 0.036 
                 0.047 
                 0.066 
                 0.109 
               
               
                 Any other individual 
                 NMT 0.1% 
                 NIL 
                 NT 
                 NT 
                 &lt;0.001 
                 0.002 
                 0.002 
                 0.012 
                 0.001 
                 0.002 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 NIL 
                 NT 
                 NT 
                 &lt;0.035 
                 0.030 
                 0.059 
                 0.219 
                 0.186 
                 0.195 
               
               
                 Dissolution 
                 NLT 80% 
                 95.30 
                 NT 
                 NT 
                 98.23 
                 94.06 
                 100.72 
                 99.47 
                 95.80 
                 99.24 
               
               
                   
                 dissolved in 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 101.50 
                 NT 
                 NT 
                 101.70 
                 98.96 
                 98.80 
                 98.54 
                 98.31 
                 99.66 
               
               
                 Microbial Limits 
                 NMT 1000 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 bacteria per gm 
               
               
                   
                 NMT 100 fungi 
                   E. coli  - absent 
               
               
                   
                 per gm. 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 18 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-II/400) stored at 30° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                   
                   
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 3 Month 
                 6 Month 
                 9 Month 
                 12 Month 
                 18 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 Orange/orange, 
                 Orange/orange, 
                 NT 
                 NT 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 Size ‘1’ hard 
                 Size ‘1’ hard 
               
               
                   
                 gelatin capsules 
                 gelatin capsules 
               
               
                   
                 containing white 
                 containing white 
               
               
                   
                 to off white 
                 to off white 
               
               
                   
                 powder, printed 
                 powder, printed 
               
               
                   
                 with logo 
                 with logo 
               
               
                   
                 in black ink. 
                 in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 10-11 
                 NT 
                 NT 
                 11-12 
                 11-12 
                 10-11 
                 10-11 
                 10-11 
                 9-10 
               
               
                 Water content (%) 
                 NMT 3% 
                 0.54 
                 NT 
                 NT 
                 1.12 
                 1.10 
                 1.02 
                 1.06 
                 1.00 
                 0.97 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.013 
                 0.036 
                 0.052 
                 0.072 
                 0.131 
                 0.185 
               
               
                 Any other 
                 NMT 0.1% 
                 NIL 
                 NT 
                 NT 
                 &lt;0.001 
                 0.004 
                 0.002 
                 0.019 
                 0.002 
                 0.003 
               
               
                 individual 
               
               
                 impurities 
               
               
                 Total 
                 NMT 1.0% 
                 NIL 
                 NT 
                 NT 
                 &lt;0.174 
                 0.232 
                 0.119 
                 0.516 
                 0.353 
                 0.452 
               
               
                 Impurities 
               
               
                 Dissolution 
                 NLT 80% 
                 95.30 
                 NT 
                 NT 
                 94.68 
                 94.65 
                 104.31 
                 97.51 
                 96.74 
                 100.15 
               
               
                   
                 dissolved in 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 101.50 
                 NT 
                 NT 
                 101.10 
                 99.21 
                 99.00 
                 98.69 
                 98.29 
                 98.94 
               
               
                 Microbial Limits 
                 NMT 1000 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 bacteria per gm 
               
               
                   
                 NMT 100 fungi 
                   E. coli  - absent 
               
               
                   
                 per gm. 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 19 
               
             
             
               
                   
               
               
                 Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs 
               
               
                 (Batch Number GBC-II/400) stored at 40° C. ± 2° C./75% ± 5% RH 
               
             
          
           
               
                 Test Performed 
                 Limits 
                 Initial 
                 1 Month 
                 2 Month 
                 3 Month 
                 6 Month 
               
               
                   
               
               
                 Appearance 
                 Orange/orange, Size ‘0’ 
                 Orange/orange, Size ‘0’ 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 hard gelatin capsules 
                 hard gelatin capsules 
               
               
                   
                 containing white to off 
                 containing white to off 
               
               
                   
                 white powder, printed 
                 white powder, printed 
               
               
                   
                 with logo in black ink. 
                 with logo in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 10-11 
                 11-12 
                 11-12 
                 10-11 
                 11-12 
               
               
                 Water content (%) 
                 NMT 3% 
                 0.54 
                 1.54 
                 1.56 
                 1.53 
                 1.52 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 0.044 
                 0.083 
                 0.104 
                 0.219 
               
               
                 Any other individual 
                 NMT 0.1% 
                 NIL 
                 0.007 
                 0.024 
                 0.023 
                 0.042 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 NIL 
                 0.051 
                 0.291 
                 0.627 
                 0.506 
               
               
                 Dissolution 
                 NLT 80% dissolved in 
                 95.30 
                 100.48 
                 91.85 
                 99.79 
                 94.10 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 101.50 
                 101.09 
                 100.38 
                 99.80 
                 99.12 
               
               
                 Microbial Limits 
                 NMT 1000 bacteria per 
                 10 CFU/gm. 
                 NT 
                 NT 
                 NT 
                 10 CFU 
               
               
                   
                 gm 
                   
                   
                   
                   
                 absent 
               
               
                   
                 NMT 100 fungi per gm. 
                   E. coli  - absent 
               
               
                   
                   E. coli  - absent 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 20 
               
             
             
               
                   
               
               
                 Stability of Neurontin ® Capsules 400 mg stored in PVC/PVdC/Aluminium packs stored at 25° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 2 Month 
                 3 Month 
                 6 Month 
                 12 Month 
                 18 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 Orange/orange, Size ‘0’ 
                 Orange/orange, 
                 NT 
                 NT 
                 NT 
                 As initial 
                 As initial 
                 NT 
                 As initial 
               
               
                   
                 hard gelatin capsules 
                 Size ‘0’ hard 
               
               
                   
                 containing white to off 
                 gelatin capsules 
               
               
                   
                 white powder, printed 
                 containing white 
               
               
                   
                 with Neurontin ® 400 mg 
                 to off white 
               
               
                   
                 logo in black ink. 
                 powder, printed 
               
               
                   
                   
                 with Neurontin ® 
               
               
                   
                   
                 400 mg 
               
               
                   
                   
                 logo in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 10-11 
                 NT 
                 NT 
                 NT 
                 10-11 
                 9-10 
                 NT 
               
               
                 Water content (%) 
                 NMT 3% 
                 NT 
                 NT 
                 NT 
                 NT 
                 1.38 
                 1.36 
                 NT 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 NT 
                 0.037 
                 0.078 
                 NT 
                 0.113 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 NT 
                 NT 
                 NT 
                 NIL 
                 0.001 
                 NT 
                 0.109 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.001 
                 NT 
                 NT 
                 NT 
                 0.051 
                 0.269 
                 NT 
                 0.378 
               
               
                 Dissolution 
                 NLT 80% dissolved in 
                 102.80 
                 NT 
                 NT 
                 NT 
                 93.84 
                 96.60 
                 NT 
                 101.29 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 98.80 
                 NT 
                 NT 
                 NT 
                 97.10 
                 98.62 
                 NT 
                 98.19 
               
               
                 Microbial Limits 
                 NMT 1000 bacteria per 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 gm 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 21 
               
             
             
               
                   
               
               
                 Stability of Neurontin ® Capsules 400 mg stored in PVC/PVdC/Aluminium packs stored at 30° C. ± 2° C./60% ± 5% RH 
               
             
          
           
               
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                   
                   
                   
               
               
                 Test Performed 
                 Limits 
                 Initial 
                 Month 
                 Month 
                 3 Month 
                 6 Month 
                 9 Month 
                 12 Month 
                 18 Month 
                 24 Month 
               
               
                   
               
               
                 Appearance 
                 Orange/orange, 
                 Orange/orange, 
                 NT 
                 NT 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 Size ‘0’ hard 
                 Size ‘0’ hard 
               
               
                   
                 gelatin capsules 
                 gelatin capsules 
               
               
                   
                 containing white 
                 containing white 
               
               
                   
                 to off white 
                 to off white 
               
               
                   
                 powder, printed 
                 powder, printed 
               
               
                   
                 with Neurontin ® 
                 with Neurontin ® 
               
               
                   
                 400 mg 
                 400 mg 
               
               
                   
                 logo in black ink. 
                 logo in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 10-11 
                 NT 
                 NT 
                 10-11 
                 10-11 
                 9-10 
                 9-10 
               
               
                 Water content (%) 
                 NMT 3% 
                 NT 
                 NT 
                 NT 
                 1.62 
                 1.38 
                 1.40 
                 1.65 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 NT 
                 NT 
                 0.016 
                 0.049 
                 0.071 
                 0.118 
                 0.152 
                 0.190 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 NT 
                 NT 
                 &lt;0.001 
                 &lt;0.001 
                 &lt;0.001 
                 &lt;0.001 
                 &lt;0.001 
                 0.278 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.001 
                 NT 
                 NT 
                 &lt;0.072 
                 &lt;0.111 
                 0.134 
                 0.329 
                 &lt;0.374 
                 0.824 
               
               
                 Dissolution 
                 NLT 80% 
                 102.80 
                 NT 
                 NT 
                 97.80 
                 93.84 
                 99.13 
                 97.78 
                 99.23 
                 101.76 
               
               
                   
                 dissolved in 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 98.80 
                 NT 
                 NT 
                 99.82 
                 97.10 
                 100.01 
                 98.79 
                 98.36 
                 100.10 
               
               
                 Microbial Limits 
                 NMT 1000 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 bacteria per gm 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 22 
               
             
             
               
                   
               
               
                 Stability of Neurontin ® Capsules 400 mg stored in PVC/PVdC/Aluminium packs stored at 40° C. ± 2° C./75% ± 5% RH 
               
             
          
           
               
                 Test Performed 
                 Limits 
                 Initial 
                 1 Month 
                 2 Month 
                 3 Month 
                 6 Month 
               
               
                   
               
               
                 Appearance 
                 Orange/orange, Size ‘0’ 
                 Orange/orange, Size ‘0’ 
                 As initial 
                 As initial 
                 As initial 
                 As initial 
               
               
                   
                 hard gelatin capsules 
                 hard gelatin capsules 
               
               
                   
                 containing white to off 
                 containing white to off 
               
               
                   
                 white powder, printed 
                 white powder, printed 
               
               
                   
                 with Neurontin ® 400 mg 
                 with Neurontin ® 400 mg 
               
               
                   
                 logo in black ink. 
                 logo in black ink. 
               
               
                 Disintegration time 
                 NMT 15 minutes 
                 10-11 
                 10-11 
                 10-11 
                 10-11 
                 10-11 
               
               
                 Water content (%) 
                 NMT 3% 
                 NT 
                 1.64 
                 1.76 
                 1.44 
                 1.40 
               
               
                 Related Substances 
               
               
                 Lactam 
                 NMT 0.3% 
                 NIL 
                 &lt;0.077 
                 0.103 
                 0.135 
                 0.283 
               
               
                 Any other individual 
                 NMT 0.1% 
                 &lt;0.001 
                 &lt;0.001 
                 &lt;0.001 
                 0.001 
                 0.004 
               
               
                 impurities 
               
               
                 Total Impurities 
                 NMT 1.0% 
                 &lt;0.001 
                 &lt;0.120 
                 &lt;0.225 
                 0.225 
                 1.084 
               
               
                 Dissolution 
                 NLT 80% dissolved in 
                 102.80 
                 99.96 
                 102.20 
                 96.41 
                 93.81 
               
               
                   
                 20 minutes 
               
               
                 Assay 
                 95-105% 
                 98.80 
                 99.13 
                 100.97 
                 98.64 
                 98.15 
               
               
                 Microbial Limits 
                 NMT 1000 bacteria per 
                 NT 
                 NT 
                 NT 
                 NT 
                 NT 
               
               
                   
                 gm 
               
               
                   
               
               
                 NT: Not Tested 
               
             
          
         
       
     
       Stability Conclusions 
       [0149]    Gabapentin capsules packed into PVC/PVdC/Aluminium blister pack have been shown to be physically and chemically stable for 36 months when stored at 25° C./50%±5% RH, 24 months when stored at 30° C.±2° C./60%±5% H and for 6 months when stored at 40° C.±2° C./75%±5% H. 
       Proposed Shelf-life 
       [0150]    The stability data generated supports the following: 
         [0151]    Proposed product shelf-life: 36 months when packed in blister packs. 
         [0152]    Labelled storage conditions: none. 
       Further Exemplary Medicinal Products 
       [0153]    Further exemplary medicinal products containing the gabapentin active are disclosed in Tables 23 and 24. 
         [0154]    Exemplary trial blends for 400 mg formulations are disclosed e.g. in Table 24. 
         [0155]    Tables 25 through 39 show stability data for these further exemplary formulations. 
       Formulation Development 
       [0156]    A capsule formulation was needed which would be linear for all three strengths. 
         [0157]    The excipients used in the preformulation studies and the coding are shown in Table 23. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 23 
               
             
             
               
                   
               
               
                 Excipients used in the pre-formulation studies 
               
             
          
           
               
                   
                 Sam- 
                 Binary 
               
               
                   
                 ple 
                 mixture 
               
               
                 Excipients 
                 code 
                 code 
               
               
                   
               
               
                 DILUENTS 
                   
                   
               
               
                 1. Dibasic Calcium Phosphate IP (NGRANULES) 
                 D1 
                 GD1 
               
               
                 2. Tribasic Calcium Phosphate IP 
                 D2 
                 GD2 
               
               
                 3. Calcium Sulphate anhydrous Ph. Eur 
                 D3 
                 GD3 
               
               
                 4. Mannitol Ph. Eur 
                 D4 
                 GD4 
               
               
                 5. Microcrystalline Cellulose (AVICEL PH 200) Ph. Eur 
                 D5 
                 GD5 
               
               
                 6. Starch IP 
                 D6 
                 GD6 
               
               
                 7. Lactose (PHARMATOSE) Ph. Eur 
                 D7 
                 GD7 
               
               
                 LUBRICANTS 
               
               
                 1. Magnesium Stearate Ph. Eur 
                 L1 
                 GL1 
               
               
                 2. Stearic Acid IP 
                 L2 
                 GL2 
               
               
                 3. Colloidal Silicon Dioxide Ph. Eur 
                 L3 
                 GL3 
               
               
                 SOLUBILIZER 
               
               
                 1. Sodium Lauryl Sulphate IP 
                 S1 
                 GS1 
               
               
                 DRUG 
               
               
                 Gabapentin (Recon) HSE 
                 G 
               
               
                 Neurontin ® Capsule 400 mg 
                 NRT 
               
               
                 B No. 0015077 
               
               
                   
               
             
          
         
       
     
         [0158]    Two trial blends (Blend I and Blend II) having the composition as shown in Table 24 were also evaluated as per the protocol for pre-formulation trials. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 24 
               
             
             
               
                   
               
               
                 Trial blends for pre-formulation studies. 
               
             
          
           
               
                   
                 Blend I 
                 Blend II 
               
             
          
           
               
                   
                 per 
                   
                 per 
                 per 50 
               
               
                   
                 capsule 
                 per 50 capsules 
                 capsule 
                 capsules 
               
               
                 Ingredients 
                 (mg) 
                 (g) 
                 (mg) 
                 (g) 
               
               
                   
               
             
          
           
               
                 Gabapentin 
                 400.00 
                 20.00 
                 400.00 
                 20.00 
               
               
                 Microcrystalline Cellulose 
                 133.00 
                 6.65 
                 133.00 
                 6.65 
               
               
                 (Avicel PH 200) 
               
               
                 Magnesium Stearate 
                 5.00 
                 0.25 
                 5.00 
                 0.25 
               
               
                 Colloidal Silicon Dioxide 
                 2.00 
                 0.10 
                 — 
                 — 
               
               
                 Sodium Lauryl Sulphate 
                 0.20 
                 0.01 
                 0.20 
                 0.01 
               
               
                   
               
             
          
         
       
     
         [0159]    All the ingredients were passed through 20 mesh screen and blended together. The results of all the pre-formulation compatibility studies are given in Tables 25 to 39, including comparative results for the drug substance (Table 39) and UK reference product (Table 38) as controls. 
       Excipient Compatibility Study Protocol Gabapentin Capsules 
       [0160]    Aim: To carry out preformulation excipient compatibility studies for Gabapentin capsules 
       Controls 
       [0161]    Gabapentin drug substance 
         [0162]    Samples retained at 4° C. 
         [0163]    Individual Excipients 
       Excipients 
     Diluents 
       [0164]    Dibasic calcium phosphate 
         [0165]    Tribasic calcium phosphate 
         [0166]    Calcium sulphate 
         [0167]    Mannitol 
         [0168]    Microcrystalline cellulose 
         [0169]    Starch IP 
         [0170]    Lactose 
       Lubricants 
       [0171]    Magnesium stearate 
         [0172]    Steric acid 
         [0173]    Colloidal silicon dioxide-to confirm the reported incompatibility 
       Solubilizer 
       [0174]    Sodium lauryl sulphate 
       Drug 
       [0175]    Gabapentin 
         [0176]    Binary mixtures to be evaluated (with and without water as necessary): 
         [0177]    1. Drug and diluents (1:0.5) 
         [0178]    2. Drug and lubricants(1:0.1) 
         [0179]    3. Drug and solubilizer (1:0.001) 
         [0180]    4. Proposed formulation from the in vitro formulation trials to confirm the extent of interactions and identify suitably stable formulations. 
         [0181]    5. Other combinations as appropriate 
       Scheme to identify chemical compatibility using DSC with confirmatory HPLC. 
       [0182]    
       
                 
         
             
             
         
       
     
         [0183]    Significant degradation is defined as 
         [0184]    1. &gt;0.5% w/w formation of lactam degradation product at conditions up to 40° C./75% RH. 
         [0185]    2. Formation of other degradants at levels &gt;0.1% w/w. 
         [0186]    3. Greater relative instability of mixture or formulation to Gabapentin drug substance and Neurotonin capsules. 
       Storage Conditions 
       [0187]    Where humidity controls are not available a defined amount of water may be added to the samples. Storage of samples was in petridishes and in stoppered glass vials. 
       Analysis of the Samples 
       [0188]    The following tests were performed at each interval: 
         [0189]    1. Appearance 
         [0190]    2. HPLC assay (as for HPLC related substances assay but calibrated for gabapentin resolution rather than for related substances) 
         [0191]    The following tests were performed at 14 and 28 day intervals. 
         [0192]    1. Appearance 
         [0193]    2. HPLC assay 
         [0194]    3. HPLC assay for related substances 
         [0195]    4. Water (to determine the hygroscopicity of the proposed formulations. 
         [0196]    DSC was carried out on initial and end point stability samples. 
       Acceptance Criteria: 
       [0197]    Similar stability profile to Neurotonin capsules, similar stability profile to Gabapentin drug substance, lactam levels &lt;0.5% w/w at 25° C. /60% RH and 40° C./75% RH after 28 days, dissolution of the proposed formulation is &gt;80% (Q) in 20 minutes at 25° C.  C/60% RH and 40° C./75% RH after 28 days. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 25 
               
               
                   
               
               
                 Pre-formulation studies, Batch Number: GD1 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 other 
               
               
                 Impurities 
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 103.4% 
                 103.3% 
                 103.5% 
                 103.2% 
                 103.2% 
                 103.1% 
                 103.2% 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 UV 
               
               
                   
                 40° C./ 
                   
                 (254 
               
               
                 Specification 
                 75% RH 
                 50° C. 
                 nm) 
               
             
          
           
               
                 Test 
                 Requirement 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 pow 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.105% 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.020% 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.013% 
                 — 
               
               
                 other 
               
               
                 Impurities 
                   
                   
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.138% 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 103.1% 
                 102.4% 
                 103.0% 
                 103.1% 
                 102.9% 
                 102.8% 
                 103.5% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 26 
               
               
                   
               
               
                 Pre-formulation studies, Batch Number: GD2 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.198% 
                 — 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 0.020% 
                 — 
                 — 
                 0.025% 
                 0.036% 
                 — 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 other 
               
               
                 Impurities 
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 0.700% 
                 0.020% 
                 — 
                 — 
                 0.025% 
                 0.234% 
                 — 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 101.6% 
                 100.8% 
                 101.0% 
                 101.8% 
                 100.5% 
                 100.4% 
                 100.9% 
               
               
                   
               
             
          
           
               
                 Specification 
                 40° C./75% RH 
                 50° C. 
                 UV 
               
             
          
           
               
                 Test 
                 Requirement 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powde 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 0.084% 
                 0.150% 
                 — 
                 — 
                 0.500% 
                 0.540% 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 Nil 
                 — 
                 — 
                 0.034% 
                 0.042% 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 Nil 
                 — 
                 — 
                 0.020% 
                 0.028% 
                 — 
               
               
                 other 
               
               
                 Impurities 
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 0.700% 
                 0.084% 
                 0.150% 
                 — 
                 — 
                 0.554% 
                 0.610% 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 100.0% 
                  99.9% 
                 100.0% 
                 100.2% 
                  99.8% 
                  99.7% 
                 101.7% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 27 
               
               
                   
               
               
                 Pre-formulation studies, Batch Number: GD3 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.008% 
                 — 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 other 
               
               
                 Impurities 
                   
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.008% 
                 — 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 104.4% 
                 104.6% 
                 104.0% 
                 104.7% 
                 104.6% 
                 104.0% 
                 103.8% 
               
               
                   
               
             
          
           
               
                 Specification 
                 40° C./75% RH 
                 50° C. 
                 UV 
               
             
          
           
               
                 Test 
                 Requirement 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 other 
               
               
                 Impurities 
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 103.1% 
                 103.5% 
                 103.8% 
                 103.6% 
                 102.1% 
                 102.5% 
                 104.5% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 28 
               
               
                   
               
               
                 Pre-formulation studies, Batch Number: GD4 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 other 
               
               
                 Impurities 
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 99.8% 
                 100.0% 
                 99.9% 
                 101.6% 
                 100.1% 
                 99.8% 
                 99.8% 
               
               
                   
               
             
          
           
               
                 Specification 
                 40° C./75% RH 
                 50° C. 
                 UV 
               
             
          
           
               
                 Test 
                 Requirement 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 other 
               
               
                 Impurities 
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 99.5% 
                 99.6% 
                 99.6% 
                 99.5% 
                 97.8% 
                 98.1% 
                 100.0% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 29 
               
               
                   
               
               
                 Pre-formulation studies, Batch Number: GD5 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 other 
               
               
                 Impurities 
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 99.1% 
                 99.3% 
                 99.2% 
                 100.6% 
                 100.3% 
                 99.1% 
                 98.9% 
               
               
                   
               
             
          
           
               
                 Specification 
                 40° C./75% RH 
                 50° C. 
                 UV 
               
             
          
           
               
                 Test 
                 Requirement 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.034% 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.008% 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 other 
               
               
                 Impurities 
                   
                   
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.042% 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 99.4% 
                 99.96% 
                 99.6% 
                 99.0% 
                 97.9% 
                  98.7% 
                 99.3% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 30 
               
             
             
               
                   
               
               
                 Pre-formulation studies, Batch Number: GD6 
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
                 50° C. 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
               
               
                   
               
               
                 De- 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                 scription 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 content 
                 0.200% 
               
               
                 b) Single 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 largest 
                 0.100% 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 other 
                 0.500% 
               
               
                 Impurities 
               
               
                 d) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 Impurities 
                 0.700% 
               
               
                 Assay 
                 95-105% 
                 98.4% 
                 — 
                 98.2% 
                 — 
                 98.0% 
                 — 
                 98.1% 
                 — 
                 97.9% 
                 — 
                 98.2% 
                 — 
                 98.1% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 31 
               
             
             
               
                   
               
               
                 Pre-formulation studies, Batch Number: GD7 
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
                 50° C. 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
               
               
                   
               
               
                 De- 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                 scription 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 content 
                 0.200% 
               
               
                 b) Single 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 0.052% 
                 0.049% 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 largest 
                 0.100% 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 other 
                 0.500% 
               
               
                 Impurities 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 0.052% 
                 0.049% 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 Impurities 
                 0.700% 
               
               
                 Assay 
                 95-105% 
                 98.9% 
                 — 
                 98.7% 
                 — 
                 98.3% 
                 — 
                 98.6% 
                 — 
                 98.2% 
                 — 
                 97.7% 
                 — 
                 98.3% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 32 
               
               
                   
               
               
                 Pre-formulation studies, Batch Number: GL1 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.010% 
                 — 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 other 
               
               
                 Impurities 
                   
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.010% 
                 — 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 100.0% 
                 100.0% 
                 100.1% 
                 100.6% 
                 100.3% 
                 98.6% 
                 98.4% 
               
               
                   
               
             
          
           
               
                 Specification 
                 40° C./75% RH 
                 50° C. 
                 UV 
               
             
          
           
               
                 Test 
                 Requirement 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 0.050% 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.009% 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 other 
               
               
                 Impurities 
                   
                   
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 0.050% 
                 — 
                 — 
                 Nil 
                 0.009% 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 98.9% 
                  99.3% 
                 99.9% 
                 98.9% 
                 98.8% 
                  98.7% 
                 100.6% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 33 
               
               
                   
               
               
                 Pre-formulation studies, Batch Number: GL2 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 other 
               
               
                 Impurities 
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 97.5% 
                 97.5% 
                 100.6% 
                 97.6% 
                 — 
                 95.8% 
                 101.2% 
               
               
                   
               
             
          
           
               
                 Specification 
                 40° C./75% RH 
                 50° C. 
                 UV 
               
             
          
           
               
                 Test 
                 Requirement 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 other 
               
               
                 Impurities 
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 96.74% 
                 — 
                 90.3% 
                 86.9% 
                 96.6% 
                 — 
                 100.6% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 34 
               
               
                   
               
               
                 Pre-formulation studies, Batch Number: GL3 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 0.095% 
                 — 
                 — 
                 0.100% 
                 0.140% 
                 — 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 other 
               
               
                 Impurities 
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 0.700% 
                 0.095% 
                 — 
                 — 
                 0.100% 
                 0.140% 
                 — 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 98.9% 
                 98.9% 
                 97.4% 
                  96.3% 
                 96.31% 
                 99.0% 
                 97.2% 
               
               
                   
               
             
          
           
               
                 Specification 
                 40° C./75% RH 
                 50° C. 
                 UV 
               
             
          
           
               
                 Test 
                 Requirement 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 0.240% 
                  0.29% 
                 — 
                 — 
                 1.260% 
                 1.050% 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 other 
               
               
                 Impurities 
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 0.700% 
                 0.240% 
                 0.240% 
                 — 
                 — 
                 1.260% 
                 1.050% 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                  96.2% 
                  96.1% 
                 99.0% 
                 97.3% 
                  95.8% 
                  95.9% 
                 99.2% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 35 
               
               
                   
               
               
                 Pre-formulation studies, Batch Number: GS1 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 other 
               
               
                 Impurities 
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 105.2% 
                 104.3% 
                 101.9% 
                 104.2% 
                 101.2% 
                 97.5% 
                 101.5% 
               
               
                   
               
             
          
           
               
                 Specification 
                 40° C./75% RH 
                 50° C. 
                 UV 
               
             
          
           
               
                 Test 
                 Requirement 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
               
               
                   
               
               
                 Description 
                 White powder 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                   
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powde 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 0.200% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 content 
               
               
                 b) Single 
                 NMT 0.100% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 largest 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 0.500% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 other 
               
               
                 Impurities 
               
               
                 d) Total 
                 NMT 0.700% 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
               
               
                 Impurities 
               
               
                 Assay 
                 95-105% 
                 97.1% 
                 100.9% 
                 99.4% 
                 104.6% 
                 103.5% 
                 100.9% 
                 105.6% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 36 
               
             
             
               
                   
               
               
                 Pre-formulation studies, Blend I 
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
                 50° C. 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
               
               
                   
               
               
                 De- 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                 scription 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.062% 
                 — 
                 — 
                 0.097% 
                 0.130% 
               
               
                 content 
                 0.200% 
               
               
                 b) Single 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.007% 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 largest 
                 0.100% 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 other 
                 0.500% 
               
               
                 Impurities 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.069% 
                 — 
                 — 
                 0.097% 
                 0.130% 
               
               
                 Impurities 
                 0.700% 
               
               
                 Assay 
                 95-105% 
                 102.5% 
                 — 
                 102.0% 
                 101.9% 
                 101.95 
                 — 
                 101.8% 
                 101.4% 
                 101.1% 
                 — 
                 101.9% 
                 101.2% 
                 101.9% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 37 
               
             
             
               
                   
               
               
                 Pre-formulation studies, Blend II 
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
                 50° C. 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
               
               
                   
               
               
                 De- 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                 scription 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.030% 
               
               
                 content 
                 0.200% 
               
               
                 b) Single 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.007% 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 largest 
                 0.100% 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 other 
                 0.500% 
               
               
                 Impurities 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.007% 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 0.030% 
               
               
                 Impurities 
                 0.700% 
               
               
                 Assay 
                 95-105% 
                 102.8% 
                 — 
                 102.5% 
                 102.4% 
                 101.1% 
                 — 
                 102.2% 
                 101.8% 
                 101.1% 
                 — 
                 102.0% 
                 101.7% 
                 102.6% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 38 
               
             
             
               
                   
               
               
                 Pre-formulation studies, Neurontin ® Capsules 400 mg, Batch Number: 0015077 
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
                 50° C. 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
               
               
                   
               
               
                 De- 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                 scription 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 
                 Nil 
                 — 
                 — 
                 0.040% 
                 Nil 
                 — 
                 — 
                 0.046% 
                 Nil 
                 — 
                 — 
                 0.058% 
                 Nil 
               
               
                 content 
                 0.200% 
               
               
                 b) Single 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 largest 
                 0.100% 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 other 
                 0.500% 
               
               
                 Impurities 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 d) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 0.040% 
                 Nil 
                 — 
                 — 
                 0.046% 
                 Nil 
                 — 
                 — 
                 0.058% 
                 Nil 
               
               
                 Impurities 
                 0.700% 
               
               
                 Assay 
                 95-105% 
                 102.7% 
                 — 
                 102.4% 
                 102.5% 
                 — 
                 — 
                 102.1% 
                 101.8% 
                 — 
                 — 
                 101.9% 
                 101.9% 
                 — 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 39 
               
             
             
               
                   
               
               
                 Pre-formulation studies, Drug Substance, Gabapentin Lot number: R 90562 
               
             
          
           
               
                 Specification 
                   
                 25° C./60% RH 
                 40° C./75% RH 
                 50° C. 
               
             
          
           
               
                 Test 
                 Requirement 
                 Initial 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
                 3 days 
                 7 days 
                 14 days 
                 28 days 
               
               
                   
               
               
                 De- 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                 scription 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
                 powder 
               
               
                 Impurities 
               
               
                 a) Lactam 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 0.004% 
                 0.004% 
               
               
                 content 
                 0.200% 
               
               
                 b) Single 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 largest 
                 0.100% 
               
               
                 individual 
               
               
                 Impurities 
               
               
                 c) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 other 
                 0.500% 
               
               
                 Impurities 
               
               
                 d) Total 
                 NMT 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
                 — 
                 — 
                 Nil 
                 Nil 
               
               
                 Impurities 
                 0.700% 
               
               
                 Asay 
                 95-105% 
                 99.4% 
                 — 
                 98.6% 
                 98.6% 
                 98.51% 
                 — 
                 98.53% 
                 98.4% 
                 97.79% 
                 — 
                 98.5% 
                 98.5% 
                 98.1% 
               
               
                   
               
               
                 — not tested 
               
             
          
         
       
     
       Preformulation Conclusions 
       [0198]    The excipient compatibility study reveals that commonly used pharmaceutical excipients are compatible with gabapentin. The excipients studied do not adversely affect the stability of gabapentin when stored at 25° C./60% RH and 40° C./75% RH. 
         [0199]    While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. It is intended, therefore, that the invention be defined by the scope of the claims that follow and that such claims be interpreted as broadly as is reasonable.