Abstract:
The invention relates to a pharmaceutical composition intended for oral administration comprising low doses of 4-((1R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine and to a composition comprising the compound.

Description:
[0001]    The present invention relates to a pharmaceutical composition intended for oral administration comprising low doses of 4-((1R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine. Moreover the invention relates to an improved binder in a composition comprising 4-((1R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine. 
       BACKGROUND OF THE INVENTION 
       [0002]    The compound which is the subject of the present invention (4-((1R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine) has the formula (I) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    International patent publication No WO 2005/016900 discloses the compound of formula I (Compound I) as a free base and its corresponding succinate and malonate salts. The compound is reported to have high affinity for dopamine D1 and D2 receptors (antagonist), for the 5-HT 2  receptor (antagonist) and for α 1  adrenoceptors. In WO 2005/016900 the compound is suggested to be useful for treatment of several diseases in the central nervous system, including psychosis, in particular schizophrenia (positive, negative, and/or depressive symptoms) or other diseases involving psychotic symptoms, such as, e.g., Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder as well other psychotic disorders or diseases associated with psychotic symptoms, e.g. mania in bipolar disorder. WO 2005/016900 also suggests the use of compound of formula I for treatment of anxiety disorders, affective disorders including depression, treatment of bipolar disorders, sleep disturbances, migraine, neuroleptic drug induced parkinsonism, as well as cocaine abuse, nicotine abuse, alcohol abuse and other abuse disorders. Other publications disclosing the compound of formula I and related compounds, having the above pharmacological profile, are EP 638 073; Bøgesø K. P.et al. J. Med. Chem., 1995, 38, page 4380-4392; and Bøgesø K. P. “Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindanes and Related Compounds”, 1998,  ISBN  87-88085-10-4 (cf. e.g. compound 69 in table 3, p 47 and in table 9A, p 101). 
     
    
     DESCRIPTION OF THE INVENTION 
       [0003]    The compound of formula I is a putative antipsychotic compound with affinity for both dopamine D1 and D2 receptors. Preclinical experiments in rats using the condition avoidance response (CAR) model (Experimental procedure previously described in: Hertel P, Olsen C K, Arnt J. Repeated administration of the neurotensin analogue NT69L induces tolerance to its suppressant effect on conditioned avoidance behaviour. Eur J Pharmacol. 2002; 439(1-3):107-11.) have indicated that the compound of formula I possesses antipsychotic activity at very low levels of D2 receptor occupancy. 
         [0004]    In a positron emission tomography (PET) study in healthy subjects using 11C-SCH23390 and  11 C-raclopride as D1 and D2 receptor tracers, it was found that the compound of formula I induces a D2 receptor occupancy of from 11 to 43% in the putamen when increasing the dose from 2 to 10 mg/day given daily for 18 days. Such level of D2 receptor occupancy is low in comparison with that of currently used antipsychotic drugs, which in general requires a D2 receptor occupancy around or exceeding 50% to be therapeutically effective (Stone J M, Davis J M, Leucht S, Pilowsky L S. Cortical Dopamine D2/D3 Receptors Are a Common Site of Action for Antipsychotic Drugs; An Original Patient Data Meta-analysis of the SPECT and PET In Vivo, Schizophr Bull. 2008 Feb. 26. [Epub in advance of print].). In the same PET study, it was found that the compound of formula I induces a D1 receptor occupancy increase from 32 to 69% in putamen when increasing the dose from 2 to 10 mg/day given daily for 18 days. Such high level of D1 occupancy is not generally seen with current used antipsychotic drugs (Farde L, Nordstrom A L, Wiesel F A, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992; 49(7):538-44.). Thus, the compound of formula I exhibits a unique ratio of D1 to D2 receptor occupancy at low daily doses. 
         [0005]    Based on the above, it is expected that the compound of formula I have clinically significant therapeutic effects in patients with schizophrenia at doses (from 4 mg/day to 14 mg/day) that induce only a low level of D2 receptor occupancy. This might well be a consequence of the high D1 receptor occupancy and the unique ratio of D1 versus D2 receptor occupancy displayed by the compound of formula I. A low D2 receptor occupancy at therapeutically effective doses will be beneficial in terms of reduced tendency to induce troublesome side effects mediated by D2 receptor blockade, including extrapyramidal side effects and hyperprolactinemia. 
         [0006]    The compound of formula I in a therapeutically effective amount of from 4-14 mg calculated as the free base is administered orally, and may be presented in any form suitable for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions. In one embodiment, a salt of the compound of formula I is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule. 
         [0007]    Methods for the preparation of solid pharmaceutical compositions or preparations are well known in the art. Thus, tablets may be prepared by mixing the active ingredient with conventional adjuvants, fillers and diluents and subsequently compressing the mixture in a suitable tabletting machine. Examples of adjuvants, fillers and diluents comprise cornstarch, lactose, talcum, magnesium stearate, gelatine, gums, and the like. Typical fillers are selected from lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose. Any other adjuvant or additive such as colourings, aroma, preservatives, etc, may also be used provided that they are compatible with the active ingredient. 
         [0008]    As already indicated, the compound 4-((1R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine has the general formula (I) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0009]    as used throughout the present description the term “compound of formula I” is intended to designate any form of the compound, such as the free base, pharmaceutically acceptable salts thereof, eg. pharmaceutically acceptable acid addition salts, such as succinate and malonate salts, hydrates or solvates of the free base or salts thereof, as well as anhydrous forms, amorphous forms, or crystalline forms. 
         [0010]    The compound of formula I to be comprised in the composition of the present invention also comprises salts thereof, typically, pharmaceutically acceptable salts. Such salts include pharmaceutical acceptable acid addition salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like. 
         [0011]    Further, the compound of formula I may exist in unsolvated form, as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered to be equivalent to unsolvated forms for the purposes of this invention. 
         [0012]    The present invention relates to a pharmaceutical composition comprising the compound of formula (I) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0013]    in a therapeutically effective amount of from 4-14 mg calculated as the free base. 
         [0014]    In a further embodiment, the composition comprising the compound of formula I is for treatment of cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse. Typical use of the composition of the invention is in the treatment of schizophrenia, such as positive symptoms of schizophrenia, or cognitive dysfunction in schizophrenia. 
         [0015]    In a further aspect the present invention relates to use of a compound of formula (I) for the preparation of a medicament for treatment of cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse, wherein the compound of formula I is present in a therapeutically effective amount of from 4-14 mg calculated as the free base. 
         [0016]    In a further aspect the present invention also relates to a method of treating cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse, comprising administering a therapeutically effective amount of from 4-14 mg calculated as the free base of the compound of formula Ito a patient in need thereof. 
         [0017]    In an embodiment of the composition, the use, or the method of treatment of the invention, the compound of formula I is formulated for oral administration, such as a tablet or capsule, typically a tablet. The composition, such as a tablet, is typically for oral administration once daily. 
         [0018]    In a further embodiment of the composition, the use, or the method of treatment, the compound of formula I is in the form of a succinate or malonate salt. Typically, the succinate salt. 
         [0019]    In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 4-12 mg. 
         [0020]    In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 5-14 mg. 
         [0021]    In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 4-6 mg, such as 5 mg. 
         [0022]    In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 6-8 mg, such as 7 mg. 
         [0023]    In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 8-10 mg. 
         [0024]    In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 10-12 mg. 
         [0025]    In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 12-14 mg, such as 14 mg. 
         [0026]    In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 5-7 mg. 
         [0027]    In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 7-9 mg. 
         [0028]    In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 9-11 mg, such as 10 mg 
         [0029]    In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 11-13 mg. 
         [0030]    When the invention relates to the use or the method of treatment then the dose indicated above of from 4-14 mg, such as 5 mg, 7 mg, 10 mg, or 14 mg, is on a daily basis. 
         [0031]    In a further embodiment of the composition, the use, or the method of treatment, the composition further comprises povidone, such as Kollidone 30 (CAS-No. 94800-10-9), or copovidone, such as Kollidone VA64 (CAS-No. 25086-89-9), as a binder. The binder is typically present in a concentration range of from 2-10% (w/w), such as 2-4%, 4-6%, 6-8%, 8-10%, 2-8%, 4-8%, 4-10%, or 6-10% (w/w). 
         [0032]    In a further aspect the present invention also relates to a pharmaceutical composition comprising the compound of formula (I) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    and povidone or copovidone as binder. Typically the binder is Kollidone VA64. 
         [0033]    In an embodiment the binder is present in a concentration range of from 2-10% (w/w). Typically in a concentration range of from 2-4%, 4-6%, 6-8%, or 8-10% (w/w). When the binder is povidone or copovidone typical fillers are selected from calcium hydrogen phosphate lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose, and preferably lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose, such as lactose. In an embodiment the filler, such as anyone of the above, is in a concentration range of from 15-50% (w/w). Typically, the filler, such as anyone of lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose, is in a concentration range of from 15-25%, 20-50%, 30-45% (w/w). 
         [0034]    In a further embodiment of the composition the compound of formula (I) is in the form of the succinate salt. 
         [0035]    Experimental 
         [0036]    The safety and efficacy of the compound of formula I in schizophrenic patient will be investigated by standard measures of efficacy (including the Positive and Negative Syndrome Scale [PANSS] and the Clinical Global Impressions scale [CGI]) and safety. After a screening period, eligible patients will be randomised in a 2:1 ratio to blinded treatment with either the compound of formula I (e.g. at doses of 5, 7, 10 and 14 mg/day) or placebo for 8 weeks. The study includes 5 parts with increasing doses of the compound of formula I and a decision to initiate the next dose level will be based on safety and tolerability assessment based on the previous part of the study. The efficacy and the safety of the compound of formula I will be evaluated in comparison to the pooled placebo group from all parts of the study. 
         [0037]    Efficacy on Cognitive Deficits in Schizophrenia 
         [0038]    The compound of formula I has been shown to possess cognition enhancing properties in preclinical models of cognitive dysfunctions. It is believed that the 5-HT6 receptor affinity of the compound of formula I is involved in the precognitive effects of the compound. Furthermore, it is believed that such pro-cognitive effect of the compound of formula I will be evident at a low level of D2 receptor occupancy, which is beneficial in terms of the side-effect profile. 
         [0039]    The effect of the compound of formula I on cognitive deficits in schizophrenic patients will be assessed in a clinical trial where eligible patients will be randomised in a 1:1 ratio to blinded treatment with flexible doses of either the compound of formula I (5 to 7 mg/day) or olanzapine (10 to 15 mg/day) for 12 weeks. The efficacy of the compound of formula I on cognitive symptoms will be assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) scale (Keefe R S, Goldberg T E, Harvey P D, Gold J M, Poe M P, Coughenour L. The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res. 2004; 68(2-3):283-97.i. Schizophr Res. 2004; 68(2-3):283-97.). 
       EXAMPLE 1 
     Preparation of Immediate Release Film-Coated Tablet Intended for Oral Administration I 
       [0040]    Pharmaceutical Development 
         [0041]    A study of the compatibility of the excipients and compound of formula I demonstrated that the components used in the tablet formulation were compatible with the compound. Based on this, a traditional wet granulation, tabletting and film-coating process was developed using standard methods and excipients. 
         [0042]    Description of Drug Product 
         [0043]    The compound of formula I is formulated as immediate release film-coated tablet intended for oral administration. Tablets containing compound of formula I in this example are made in two strengths, 5 and 7 mg. The product containing compound of formula I is a white film-coated tablet encapsulated in a brownish red hard capsule. Other strengths, such as 4, 6, 8, 9, 10, 11, 12, 13, or 14 mg, may be prepared in the same manner. 
         [0044]    Composition 
         [0045]    The compositions of the tablets 5 mg and 7 mg are given below in Table 1. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Composition of tablets 5 mg and 7 mg 
               
             
          
           
               
                   
                 Quantity per Unit 
                   
                 Reference to 
               
             
          
           
               
                 Name of Ingredient 
                 5 mg 
                 7 mg 
                 Function 
                 Standard 1   
               
               
                   
               
             
          
           
               
                 DRUG SUBSTANCE 
                   
                   
                   
                   
                   
                   
               
               
                 compound of formula I succinate 
                 6.665 
                 mg 
                 9.331 
                 mg 
                 Active ingredient 
                 In-house spec. 
               
               
                 corresponding to compound of 
                 5 
                 mg 
                 7 
                 mg 
               
               
                 formula I 
               
               
                 EXCIPIENTS 
               
               
                 Tablet core: 
               
               
                 Calcium hydrogen phosphate, 
                 37.990 
                 mg 
                 36.213 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 anhydrous 
               
               
                 Maize starch 
                 18.995 
                 mg 
                 18.106 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 Copovidone 
                 3.35 
                 mg 
                 3.35 
                 mg 
                 Binder 
                 Ph. Eur. 
               
             
          
           
               
                 Water, purified 2   
                 q.s. 
                 q.s. 
                 Granulation liquid 
                 Ph. Eur. 
               
             
          
           
               
                 Cellulose, microcrystalline 
                 25 
                 mg 
                 25 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 Croscarmellose sodium 
                 3 
                 mg 
                 3 
                 mg 
                 Disintegrant 
                 Ph. Eur. 
               
               
                 Talc 
                 4 
                 mg 
                 4 
                 mg 
                 Lubricant 
                 Ph. Eur. 
               
               
                 Magnesium stearate 
                 1 
                 mg 
                 1 
                 mg 
                 Lubricant 
                 Ph. Eur. 
               
               
                 Weight of each tablet core 
                 100 
                 mg 
                 100 
                 mg 
               
               
                 Film-coating: 
               
               
                 Opadry Y-1-7000 white 
               
               
                 consisting of: 
               
               
                 Hypromellose (5 mPa · s.) 
                 1.563 
                 mg 
                 1.563 
                 mg 
                 Film former 
                 Ph. Eur. 
               
               
                 Macrogol 400 
                 0.156 
                 mg 
                 0.156 
                 mg 
                 Plasticizer 
                 Ph. Eur. 
               
               
                 Titanium dioxide (E171) 
                 0.781 
                 mg 
                 0.781 
                 mg 
                 Pigment 
                 Ph. Eur. 
               
             
          
           
               
                 Water, purified 2   
                 q.s. 
                 q.s. 
                 Solvent 
                 Ph. Eur. 
               
             
          
           
               
                 Weight of each film-coated tablet 
                 102.5 
                 mg 
                 102.5 
                 mg 
               
             
          
           
               
                 Magnesium stearate 
                 q.s. 
                 q.s. 
                 Lubricant 
                 Ph. Eur. 
               
               
                   
               
               
                   1 The current pharmacopoeia is used 
               
               
                   2 Volatile material 
               
             
          
         
       
     
         [0046]    The batch compositions for a representative batch size of 10,000 tablets are presented in Table 2. 
         [0000]    
       
         
               
             
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Batch composition for film-coated tablets (Batch size 10,000 tablets) 
               
             
          
           
               
                   
                 Strength 
               
             
          
           
               
                   
                 5 mg 
                 7 mg 
               
             
          
           
               
                   
                   
                 % w/w 
                   
                 % 
               
               
                   
                   
                 (per 
                   
                 w/w 
               
               
                   
                 Quantity 
                 tablet 
                 Quantity 
                 (per 
               
               
                 Ingredients 
                 (g) 
                 core) 
                 (g) 
                 tablet core) 
               
               
                   
               
             
          
           
               
                 Tablet core: 
                   
                   
                   
                   
               
               
                 compound of formula I 
                 66.65 
                 6.665 
                 93.31 
                 9.331 
               
               
                 succinate 
               
               
                 Calcium hydrogen 
                 379.90 
                 37.990 
                 362.13 
                 36.213 
               
               
                 phosphate, anhydrous 
               
               
                 Maize starch 
                 189.95 
                 18.995 
                 181.06 
                 18.106 
               
               
                 Copovidone 
                 33.5 
                 3.35 
                 33.5 
                 3.35 
               
               
                 Water, purified 1   
                 q.s. 
                 — 
                 q.s. 
                 — 
               
               
                 Cellulose, 
                 250 
                 25 
                 250 
                 25 
               
               
                 microcrystalline 
               
               
                 Croscarmellose sodium 
                 30 
                 3 
                 30 
                 3 
               
               
                 Talc 
                 40 
                 4 
                 40 
                 4 
               
               
                 Magnesium stearate 
                 10 
                 1 
                 10 
                 1 
               
             
          
           
               
                 Weight of tablet core 
                   100 mg 
                   100 mg 
               
               
                 Film coating: 
               
             
          
           
               
                 Opadry Y-1-7000 white 
                 25 
                 2.5 
                 25 
                 2.5 
               
               
                 Water, purified 1   
                 q.s. 
                 — 
                 q.s. 
                 — 
               
             
          
           
               
                 Weight of film-coated 
                 102.5 mg 
                 102.5 mg 
               
               
                 tablet 
               
               
                   
               
             
          
         
       
     
         [0047]    Description of Manufacturing Process and Process Controls 
         [0048]    The method of granulation is a traditional wet granulation process using copovidone (Kollidone VA64) as a dry binder and water as granulation liquid. In the 10-litre PMA1 high shear mixer the process is as follows for a 2 kg batch: 
         [0049]    Mix compound of formula I succinate, anhydrous calcium hydrogen phosphate, maize starch and copovidone for 2 minutes at 500 rpm. 
         [0050]    Add purified water to initiate agglomeration. 
         [0051]    Granulate at 800 rpm for approximately 4 minutes, so a suitable granule size is achieved. 
         [0052]    Sieve the wet granules. 
         [0053]    Dry the granules in a tray dryer at 50° C., until the product has a relative humidity (RH) of 25-55%RH. 
         [0054]    Sieve the dried granules. 
         [0055]    Mix the granules with microcrystalline cellulose, croscarmellose sodium and talc in a mixer. 
         [0056]    Ad magnesium stearate to the mixer and mix. 
         [0057]    Compress the granulate into tablets on a tablet compressing machine. 
         [0058]    Film-coat the tablet cores in a film coater, using the process parameters given in table 3. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Equipment and process conditions for the coating process. 
               
             
          
           
               
                   
                   
                 Spray 
                 Inlet air 
                   
                   
               
               
                   
                 Load 
                 rate 
                 flow 
                 Inlet air 
                 Outlet air 
               
               
                 Equipment 
                 (g) 
                 (g/min) 
                 (m 3 /h) 
                 temp. (° C.) 
                 temp. (° C.) 
               
               
                   
               
               
                 Compu Lab 
                 1360-1500 
                 10 
                 500 
                 60 
                 58 
               
               
                 15″ 
               
               
                   
               
             
          
         
       
     
         [0059]    A flow diagram of the manufacturing process and process controls is shown in  FIG. 1 . 
         [0060]    Unexpected Effects of Binder in the Tablet Formulation 
         [0061]    In order to optimise the agglomeration process, two different tablet formulations was produced and their effect on the chemical stability of compound of formula I was evaluated. The composition of these tablets are given in table 4, and the manufacturing process, was similar to the one described above: 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Batch composition of film-coated tablets with 2 different binders (Batch 
               
               
                 size 10,000 tablets) 
               
             
          
           
               
                   
                 Strength 
                   
               
               
                   
                 2.5 mg 
               
             
          
           
               
                   
                   
                 % w/w (per 
                 % w/w (per 
               
               
                   
                 Ingredients 
                 tablet core) 
                 tablet core) 
               
               
                   
                   
               
             
          
           
               
                   
                 Tablet core: 
                   
                   
               
               
                   
                 compound of formula I 
                 2.67 
                 2.67 
               
               
                   
                 succinate 
               
               
                   
                 Calcium hydrogen 
                 40.66 
                 40.66 
               
               
                   
                 phosphate, anhydrous 
               
               
                   
                 Maize starch 
                 20.33 
                 20.33 
               
               
                   
                 Copovidone 
                 3.3 
                 0.0 
               
               
                   
                 Maltodextrin 
                 0.00 
                 3.35 
               
               
                   
                 Water, purified 1   
                 — 
                 — 
               
               
                   
                 Cellulose, microcrystalline 
                 26.0 
                 26.0 
               
               
                   
                 Croscarmellose sodium 
                 3.0 
                 3.0 
               
               
                   
                 Talc 
                 3.0 
                 3.0 
               
               
                   
                 Magnesium stearate 
                 1.0 
                 1.0 
               
             
          
           
               
                   
                 Weight of tablet core 
                 125 mg 
               
               
                   
                   
               
             
          
         
       
     
         [0062]    The use of copovidone as binder leads to tablets with better pharmaceutical technical properties, e.g. the cabability of producing harder tablets with low loss on friability without compromising the disintegration time, as demonstrated in table 5: 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Comparision of pharmaceutical technical data for tablets containing 
               
               
                 compound of formula I succinate with the composition given in table 4 
               
             
          
           
               
                 Copovidone 
                 Maltodextrin 
               
             
          
           
               
                 Applied 
                   
                   
                 Applied 
                   
                   
               
               
                 compression 
                 Friability 
                 Disintegration 
                 compression 
               
               
                 force (N) 
                 (%, w/w) 
                 time 
                 force (N) 
                 Friability (%) 
               
               
                   
               
             
          
           
               
                 86 
                 0.14 
                 44 sec 
                 36 
                 0.69 
                 43 sec 
               
               
                 108 
                 0.16 
                 1 min 14 sec 
                 47 
                 0.51 
                 1 min 13 sec 
               
               
                 120 
                 0.18 
                 1 min 52 sec 
                 51 
                 0.43 
                 1 min 42 sec 
               
               
                 130 
                 0.22 
                 2 min 09 sec 
                 59 
                 0.23 
                 1 min 59 sec 
               
               
                   
               
             
          
         
       
     
         [0063]    Furthermore, the difference in binder lead to surprising stability differences as demonstrated in table 6 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Decomposition of compound of formula I succinate, in formulations 
               
               
                 where maltodextrin and copovidon are used as binder, composition 
               
               
                 of tablets given in table 4. 
               
             
          
           
               
                   
                 Total decomposition (%) of 
                   
               
               
                   
                 compound of formula I 
               
             
          
           
               
                   
                 Treatment 
                 Copovidone 
                 Maltodextrin 
               
               
                   
                   
               
             
          
           
               
                   
                 Initial analysis 
                 &lt;0.05 
                 &lt;0.05 
               
               
                   
                 After autoclavation 
                 0.91 
                 1.1 
               
               
                   
                 80° C. for 48 hours 
                 0.99 
                 2.0 
               
               
                   
                 80° C. for 120 hours 
                 1.4 
                 3.7 
               
               
                   
                 40° C./75% RH for 3 
                 &lt;0.05 
                 &lt;0.05 
               
               
                   
                 weeks 
               
               
                   
                 60° C. for 3 weeks 
                 0.95 
                 1.41 
               
               
                   
                   
               
             
          
         
       
     
       EXAMPLE 2 
     Preparation of Immediate Release Film-Coated Tablet Intended for Oral Administration II 
       [0064]    Pharmaceutical Development 
         [0065]    A study of the compatibility of the excipients and Compound I demonstrated that the components used in the tablet formulation were compatible with the compound. Based on this, a traditional wet granulation, tabletting and film-coating process was developed using standard methods and excipients. 
         [0066]    Description of Drug Product 
         [0067]    Compound I is formulated as immediate release film-coated tablet intended for oral administration. Tablets containing compound of formula I in this example are made in two strengths, 2.5 and 5 mg. The product containing compound of formula I is a white film-coated tablet encapsulated in a brownish red hard capsule. Other strengths, such as 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mg, may be prepared in the same manner. 
         [0068]    Composition 
         [0069]    The compositions of the tablets 2.5 mg and 5 mg are given below in Table 7. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Composition of tablets 2.5 mg and 5 mg (calcium phosphate form.) 
               
             
          
           
               
                   
                 Quantity per Unit 
                   
                 Reference to 
               
             
          
           
               
                 Name of Ingredient 
                 2.5 mg 
                 5 mg 
                 Function 
                 Standard 1   
               
               
                   
               
             
          
           
               
                 DRUG SUBSTANCE 
                   
                   
                   
                   
                   
                   
               
               
                 Compound I, succinate 
                 3.333 
                 mg 
                 6.667 
                 mg 
                 Active ingredient 
                 In-house spec. 
               
               
                 Corresponding to Compound I 
                 2.5 
                 mg 
                 5 
                 mg 
               
               
                 EXCIPIENTS 
               
               
                 Tablet core: 
               
               
                 Calcium hydrogen phosphate, 
                 40.000 
                 mg 
                 80.000 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 anhydrous 
               
               
                 Maize starch 
                 20.000 
                 mg 
                 40.000 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 Copovidone 
                 5.00 
                 mg 
                 10.00 
                 mg 
                 Binder 
                 Ph. Eur. 
               
             
          
           
               
                 Water, purified 2   
                 q.s. 
                 q.s. 
                 Granulation liquid 
                 Ph. Eur. 
               
             
          
           
               
                 Cellulose, microcrystalline 
                 26.17 
                 mg 
                 52.34 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 Croscarmellose sodium 
                 3 
                 mg 
                 6 
                 mg 
                 Disintegrant 
                 Ph. Eur. 
               
               
                 Talc 
                 1.5 
                 mg 
                 3 
                 mg 
                 Lubricant 
                 Ph. Eur. 
               
               
                 Magnesium stearate 
                 1 
                 mg 
                 2 
                 mg 
                 Lubricant 
                 Ph. Eur. 
               
               
                 Weight of each tablet core 
                 100 
                 mg 
                 200 
                 mg 
               
               
                 Film-coating: 
               
               
                 Opadry Y-1-7000 white 
               
               
                 consisting of: 
               
               
                 Hypromellose (5 mPa · s.) 
                 1.563 
                 mg 
                 3.126 
                 mg 
                 Film former 
                 Ph. Eur. 
               
               
                 Macrogol 400 
                 0.156 
                 mg 
                 0.312 
                 mg 
                 Plasticizer 
                 Ph. Eur. 
               
               
                 Titanium dioxide (E171) 
                 0.781 
                 mg 
                 1.562 
                 mg 
                 Pigment 
                 Ph. Eur. 
               
             
          
           
               
                 Water, purified 2   
                 q.s. 
                 q.s. 
                 Solvent 
                 Ph. Eur. 
               
             
          
           
               
                 Weight of each film-coated tablet 
                 102.5 
                 mg 
                 205 
                 mg 
               
             
          
           
               
                 Magnesium stearate 
                 q.s. 
                 q.s. 
                 Lubricant 
                 Ph. Eur. 
               
               
                   
               
               
                   1 The current pharmacopoeia is used 
               
               
                   2 Volatile material 
               
             
          
         
       
     
         [0070]    The batch compositions for a representative batch size of 10,000 tablets are presented in Table 8. 
         [0000]    
       
         
               
             
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Batch composition for film-coated tablets (Batch size 10,000 tablets) 
               
             
          
           
               
                   
                 Strength 
               
             
          
           
               
                   
                 2.5 mg 
                 5 mg 
               
             
          
           
               
                   
                   
                 % w/w 
                   
                 % w/w 
               
               
                   
                 Quantity 
                 (per tablet 
                 Quantity 
                 (per tablet 
               
               
                 Ingredients 
                 (g) 
                 core) 
                 (g) 
                 core) 
               
               
                   
               
             
          
           
               
                 Tablet core: 
                   
                   
                   
                   
               
               
                 Compound of formula I 
                 33.33 
                 3.333 
                 66.67 
                 3.333 
               
               
                 succinate 
               
               
                 Calcium hydrogen 
                 400.00 
                 40.000 
                 800.00 
                 40.000 
               
               
                 phosphate, anhydrous 
               
               
                 Maize starch 
                 200.00 
                 20.000 
                 400.00 
                 20.000 
               
               
                 Copovidone 
                 50.0 
                 5.00 
                 100.0 
                 5.00 
               
               
                 Water, purified 1   
                 q.s. 
                 — 
                 q.s. 
                 — 
               
               
                 Cellulose, 
                 261.7 
                 26.17 
                 523.4 
                 26.17 
               
               
                 microcrystalline 
               
               
                 Croscarmellose sodium 
                 30 
                 3 
                 60 
                 3 
               
               
                 Talc 
                 15 
                 1.5 
                 30 
                 1.5 
               
               
                 Magnesium stearate 
                 10 
                 1 
                 20 
                 1 
               
             
          
           
               
                 Weight of tablet core 
                   100 mg 
                 200 mg 
               
               
                 Film coating: 
               
             
          
           
               
                 Opadry Y-1-7000 white 
                 25 
                 2.5 
                 50 
                 2.5 
               
               
                 Water, purified 1   
                 q.s. 
                 — 
                 q.s. 
                 — 
               
             
          
           
               
                 Weight of film-coated 
                 102.5 mg 
                 205 mg 
               
               
                 tablet 
               
               
                   
               
             
          
         
       
     
         [0071]    Manufacturing process and process controls is as in Example 1. 
         [0072]    A flow diagram of the manufacturing process and process controls is shown in  FIG. 1 . 
         [0073]    Unexpected Effects of Binder in the Tablet Formulation II 
         [0074]    In order to optimise the agglomeration process, one tablet formulation (2.5 mg) for each binder was produced and the effect of binder on the chemical stability of Compound I was evaluated. The composition of these tablets is given in table 9, and the manufacturing process, was similar to the one described above. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
             
               
               
               
               
               
             
               
               
             
               
               
               
               
             
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 9 
               
               
                   
               
               
                 Batch composition of film-coated tablets with 7 different binders (Batch 
               
               
                 size 10,000 tablets) 
               
               
                 Strength 2.5 mg 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 % w/w (per 
                 % w/w (per 
                 % w/w (per 
                 % w/w (per 
               
               
                   
                 tablet core) 
                 tablet core) 
                 tablet core) 
                 tablet core) 
               
             
          
           
               
                   
                 Formulation no.: 
               
             
          
           
               
                 Ingredients 
                 1 
                 2 
                 3 
                 4 
               
               
                   
               
               
                 Tablet core: 
               
               
                 Compound of formula I 
                 3.33 
                 3.33 
                 3.33 
                 3.33 
               
               
                 succinate 
               
               
                 Calcium hydrogen 
                 40.66 
                 40.66 
                 40.66 
                 40.66 
               
               
                 phosphate, anhydrous 
               
               
                 Maize starch 
                 20.33 
                 20.33 
                 20.33 
                 20.33 
               
               
                 Pregelatinized starch 
                 5.0 
                 0.0 
                 0.0 
                 0.0 
               
               
                 Hypromellose 
                 0.0 
                 5.0 
                 0.0 
                 0.0 
               
               
                 Povidone 
                 0.0 
                 0.0 
                 5.0 
                 0.0 
               
               
                 Methylcellulose 
                 0.0 
                 0.0 
                 0.0 
                 5.0 
               
               
                 Water, purified 1   
                 — 
                 — 
                 — 
                 — 
               
               
                 Cellulose, microcrystalline 
                 25.2 
                 25.2 
                 25.2 
                 25.2 
               
               
                 Croscarmellose sodium 
                 3.0 
                 3.0 
                 3.0 
                 3.0 
               
               
                 Talc 
                 1.5 
                 1.5 
                 1.5 
                 1.5 
               
               
                 Magnesium stearate 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
               
             
          
           
               
                 Weight of tablet core 
                 100 mg 
               
               
                   
               
             
          
           
               
                   
                 % w/w (per tablet 
                 % w/w (per tablet 
                 % w/w (per tablet 
               
               
                   
                 core) 
                 core) 
                 core) 
               
             
          
           
               
                   
                 Formulation no.: 
               
             
          
           
               
                 Ingredients 
                 5 
                 6 
                 7 
               
               
                   
               
               
                 Tablet core: 
               
             
          
           
               
                 compound of 
                 3.33 
                   
                 3.33 
                   
                 2.67 
                   
               
               
                 formula I succinate 
               
               
                 Calcium hydrogen 
                 40.66 
                   
                 40.00 
                   
                 40.66 
               
               
                 phosphate, 
               
               
                 anhydrous 
               
               
                 Maize starch 
                 20.33 
                   
                 20.00 
                   
                 20.33 
               
               
                 Sucrose 
                 5.0 
                   
                 0.0 
                   
                 0.0 
               
               
                 Copovidone 
                 0.0 
                   
                 5.0 
                   
                 0.0 
               
               
                 Maltodextrine 
                 0.0 
                   
                 0.0 
                   
                 3.35 
               
             
          
           
               
                 Water, purified 1   
                 — 
                 — 
                 — 
               
             
          
           
               
                 Cellulose, 
                 25.2 
                   
                 26.2 
                   
                 26.0 
                   
               
               
                 microcrystalline 
               
               
                 Croscarmellose 
                 3.0 
                   
                 3.0 
                   
                 3.0 
               
               
                 sodium 
               
               
                 Talc 
                 1.5 
                   
                 1.5 
                   
                 3.0 
               
               
                 Magnesium 
                 1.0 
                   
                 1.0 
                   
                 1.0 
               
               
                 stearate 
                   
                   
               
               
                 Weight of tablet 
                 100 
                 mg 
                 100 
                 mg 
                 125 
                 mg 
               
               
                 core 
               
               
                   
               
             
          
         
       
     
         [0075]    The use of copovidone as binder (Formulation No. 6) leads to tablets with good pharmaceutical technical properties, e.g. a relative long disintegration time permitting the tablets to be swallowed as whole tablets (as demonstrated in table 10) and acceptable stability data (as demonstrated in table 11): 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 Comparision of pharmaceutical technical data for tablets containing 
               
               
                 compound of formula I succinate with the composition given in table 9. 
               
             
          
           
               
                 Pharm. 
                 Weight of the 
                   
                 Friability 
                 Disintegration 
               
               
                 Technical data 
                 tablet core 
                 Hardness 
                 (16 min) 
                 (sec.) 
               
               
                   
               
             
          
           
               
                 Form. 1 
                 100 mg 
                 46 N 
                 0.5% 
                 11 
               
               
                 Form. 2 
                 100 mg 
                 50 N 
                 0.6% 
                 22 
               
               
                 Form. 3 
                 100 mg 
                 48 N 
                 0.5% 
                 35 
               
               
                 Form. 4 
                 100 mg 
                 53 N 
                 — 
                 39 
               
               
                 Form. 5 
                 100 mg 
                 63 N 
                 — 
                 45 
               
               
                 Form. 6 
                 100 mg 
                 37 N 
                 0.5% 
                 112 
               
               
                 Form. 7 
                 125 mg 
                 36 N 
                 0.7% 
                 43 
               
               
                   
               
             
          
         
       
     
         [0076]    Some differences in the stability of the products containing different binders can be seen in table 11 (next page). 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
               
               
             
               
             
               
               
               
             
           
               
                 TABLE 11 
               
               
                   
               
             
             
               
                 Decomposition of compound of formulation 1 to 6 - 
               
               
                 different binders are used, composition of tablets 
               
               
                 given in table 9 
               
             
          
           
               
                   
                 Total decomposition (%) of API 
               
             
          
           
               
                 Treatment 
                 Form. 1 
                 Form. 2 
                 Form. 3 
                 Form. 4 
                 Form. 5 
                 Form. 6 
               
               
                   
               
               
                 Initial analysis 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 Autoclavation 
                 0.43 
                 0.44 
                 0.94 
                 0.51 
                 0.99 
                 0.53 
               
               
                 80° C. for 48 
                 2.6 
                 3.2 
                 9.7 
                 3.4 
                 1.4 
                 5.4 
               
               
                 hours (open) 
               
               
                 80° C. for 48 
                 5.3 
                 1.7 
                 5.2 
                 2.0 
                 1.9 
                 5.9 
               
               
                 hours (closed) 
               
               
                 80° C. for 144 
                 5.0 
                 6.8 
                 20.0 
                 6.6 
                 2.6 
                 12.7 
               
               
                 hours (open) 
               
               
                 80° C. for 144 
                 2.7 
                 4.5 
                 9.0 
                 3.8 
                 5.1 
                 2.9 
               
               
                 hours (closed) 
               
               
                 40° C./ 
                 0.17 
                 0.18 
                 0.25 
                 0.25 
                 0.17 
                 0.32 
               
               
                 75% RH 
               
               
                 for 1 week 
               
               
                 40° C./ 
                 0.18 
                 0.28 
                 0.34 
                 0.30 
                 0.25 
                 0.31 
               
               
                 75% RH 
               
               
                 for 3 weeks 
               
               
                 40° C./ 
                 0.25 
                 0.30 
                 0.43 
                 0.35 
                 0.35 
                 0.41 
               
               
                 75% RH 
               
               
                 for 6 weeks 
               
               
                 40° C./ 
                 0.30 
                 0.36 
                 0.70 
                 0.38 
                 0.54 
                 0.66 
               
               
                 75% RH 
               
               
                 for 10 weeks 
               
               
                 40° C./ 
                 0.33 
                 0.36 
                 0.80 
                 0.41 
                 0.60 
                 0.75 
               
               
                 75% RH 
               
               
                 for 12 weeks 
               
               
                 60° C. for 1 
                 0.59 
                 0.55 
                 1.1 
                 0.61 
                 0.28 
                 0.69 
               
               
                 week 
               
               
                 60° C. for 3 
                 1.6 
                 1.5 
                 3.5 
                 1.6 
                 0.48 
                 1.8 
               
               
                 weeks 
               
               
                 60° C. for 6 
                 2.4 
                 2.4 
                 6.2 
                 2.5 
                 0.88 
                 2.9 
               
               
                 weeks 
               
               
                 60° C. for 10 
                 3.5 
                 3.6 
                 9.6 
                 3.9 
                 1.2 
                 4.6 
               
               
                 weeks 
               
               
                 60° C. for 12 
                 3.7 
                 3.8 
                 10.3 
                 4.2 
                 1.4 
                 5.0 
               
               
                 weeks 
               
               
                   
               
             
          
           
               
                 Decomposition of compound of formulation 7, in formulation 
               
               
                 where maltodextrin is used as binder, composition of tablets 
               
               
                 given in table 9 
               
             
          
           
               
                   
                 Treatment 
               
               
                   
                   
               
               
                   
                 Binder 
                 Maltodextrin (form. 7) 
               
               
                   
                 Initial analysis 
                 &lt;0.05 
               
               
                   
                 After autoclavation 
                 1.1 
               
               
                   
                 80° C. for 48 hours 
                 2.0 
               
               
                   
                 80° C. for 120 hours 
                 3.7 
               
               
                   
                 40° C./75% RH for 3 weeks 
                 &lt;0.05 
               
               
                   
                 60° C. for 3 weeks 
                 1.41 
               
               
                   
                   
               
               
                   
                 ND = Not detected 
               
             
          
         
       
     
       EXAMPLE 3 
     Preparation of Immediate Release Film-Coated Tablet Intended for Oral Administration III 
       [0077]    Pharmaceutical Development 
         [0078]    A study of the compatibility of the excipients and Compound I demonstrated that the components used in the tablet formulation were compatible with the compound. Based on this, a traditional wet granulation, tabletting and film-coating process was developed using standard methods and excipients. 
         [0079]    Description of Drug Product 
         [0080]    Compound I is formulated as immediate release film-coated tablet intended for oral administration. Tablets containing compound of formula I in this example are made in two strengths, 2.5 and 5 mg. The product containing compound of formula I is a white film-coated tablet encapsulated in a brownish red hard capsule. Other strengths, such as 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mg, may be prepared in the same manner. 
         [0081]    Composition 
         [0082]    The compositions of the tablets 2.5 mg and 5 mg are given below in Table 12 and Table 13. 
         [0083]    Manufacturing process and process controls is as in Example 1. A flow diagram of the manufacturing process and process controls is shown in  FIG. 1 . 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                 Composition of tablets 2.5 mg and 5 mg (calcium phosphate 
               
               
                 formulation) 
               
             
          
           
               
                   
                 Quantity per Unit 
                   
                 Reference to 
               
             
          
           
               
                 Name of Ingredient 
                 2.5 mg 
                 5 mg 
                 Function 
                 Standard 1   
               
               
                   
               
             
          
           
               
                 DRUG SUBSTANCE 
                   
                   
                   
                   
                   
                   
               
               
                 Compound I, succinate 
                 3.333 
                 mg 
                 6.667 
                 mg 
                 Active ingredient 
                 In-house spec. 
               
               
                 Corresponding to Compound I 
                 2.5 
                 mg 
                 5 
                 mg 
               
               
                 EXCIPIENTS 
               
               
                 Tablet core: 
               
               
                 Calcium hydrogen phosphate, 
                 40.000 
                 mg 
                 40.000 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 anhydrous 
               
               
                 Maize starch 
                 20.000 
                 mg 
                 20.000 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 Copovidone 
                 5.00 
                 mg 
                 5.00 
                 mg 
                 Binder 
                 Ph. Eur. 
               
             
          
           
               
                 Water, purified 2   
                 q.s. 
                 q.s. 
                 Granulation liquid 
                 Ph. Eur. 
               
             
          
           
               
                 Cellulose, microcrystalline 
                 26.17 
                 mg 
                 22.83 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 Croscarmellose sodium 
                 3 
                 mg 
                 3 
                 mg 
                 Disintegrant 
                 Ph. Eur. 
               
               
                 Talc 
                 1.5 
                 mg 
                 1.5 
                 mg 
                 Lubricant 
                 Ph. Eur. 
               
               
                 Magnesium stearate 
                 1 
                 mg 
                 1 
                 mg 
                 Lubricant 
                 Ph. Eur. 
               
               
                 Weight of each tablet core 
                 100 
                 mg 
                 100 
                 mg 
               
               
                 Film-coating: 
               
               
                 Opadry Y-1-7000 white 
               
               
                 consisting of: 
               
               
                 Hypromellose (5 mPa · s.) 
                 1.563 
                 mg 
                 1.563 
                 mg 
                 Film former 
                 Ph. Eur. 
               
               
                 Macrogol 400 
                 0.156 
                 mg 
                 0.156 
                 mg 
                 Plasticizer 
                 Ph. Eur. 
               
               
                 Titanium dioxide (E171) 
                 0.781 
                 mg 
                 0.781 
                 mg 
                 Pigment 
                 Ph. Eur. 
               
             
          
           
               
                 Water, purified 2   
                 q.s. 
                 q.s. 
                 Solvent 
                 Ph. Eur. 
               
             
          
           
               
                 Weight of each film-coated tablet 
                 102.5 
                 mg 
                 102.5 
                 mg 
                 Lubricant 
                 Ph. Eur. 
               
             
          
           
               
                 Magnesium stearate 
                 q.s. 
                 q.s. 
               
               
                   
               
               
                   1 The current pharmacopoeia is used 
               
               
                   2 Volatile material 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 Composition of tablets 2.5 mg and 5 mg (lactose formulation) 
               
             
          
           
               
                   
                 Quantity per Unit 
                   
                 Reference to 
               
             
          
           
               
                 Name of Ingredient 
                 2.5 mg 
                 5 mg 
                 Function 
                 Standard 1   
               
               
                   
               
             
          
           
               
                 DRUG SUBSTANCE 
                   
                   
                   
                   
                   
                   
               
               
                 Compound I, succinate 
                 3.333 
                 mg 
                 6.667 
                 mg 
                 Active ingredient 
                 In-house spec. 
               
               
                 Corresponding to Compound I 
                 2.5 
                 mg 
                 5 
                 mg 
               
               
                 EXCIPIENTS 
               
               
                 Tablet core: 
               
               
                 Lactose 
                 39.330 
                 mg 
                 39.330 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 Maize starch 
                 15.000 
                 mg 
                 15.000 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 Copovidone 
                 3.35 
                 mg 
                 3.35 
                 mg 
                 Binder 
                 Ph. Eur. 
               
             
          
           
               
                 Water, purified 2   
                 q.s. 
                 q.s. 
                 Granulation liquid 
                 Ph. Eur. 
               
             
          
           
               
                 Cellulose, microcrystalline 
                 34.99 
                 mg 
                 31.65 
                 mg 
                 Filler 
                 Ph. Eur. 
               
               
                 Croscarmellose sodium 
                 3 
                 mg 
                 3 
                 mg 
                 Disintegrant 
                 Ph. Eur. 
               
               
                 Magnesium stearate 
                 1 
                 mg 
                 1 
                 mg 
                 Lubricant 
                 Ph. Eur. 
               
               
                 Weight of each tablet core 
                 100 
                 mg 
                 100 
                 mg 
               
               
                 Film-coating: 
               
               
                 Opadry Y-1-7000 white 
               
               
                 consisting of: 
               
               
                 Hypromellose (5 mPa · s.) 
                 1.563 
                 mg 
                 1.563 
                 mg 
                 Film former 
                 Ph. Eur. 
               
               
                 Macrogol 400 
                 0.156 
                 mg 
                 0.156 
                 mg 
                 Plasticizer 
                 Ph. Eur. 
               
               
                 Titanium dioxide (E171) 
                 0.781 
                 mg 
                 0.781 
                 mg 
                 Pigment 
                 Ph. Eur. 
               
             
          
           
               
                 Water, purified 2   
                 q.s. 
                 q.s. 
                 Solvent 
                 Ph. Eur. 
               
             
          
           
               
                 Weight of each film-coated tablet 
                 102.5 
                 mg 
                 102.5 
                 mg 
               
             
          
           
               
                 Magnesium stearate 
                 q.s. 
                 q.s. 
                 Lubricant 
                 Ph. Eur. 
               
               
                   
               
               
                   1 The current pharmacopoeia is used 
               
               
                   2 Volatile material