STABLE PHARMACEUTICAL COMPOSITION OF 3-(HYDROXYMETHYL)-5,5-DIPHENYLHYDANTOIN DISODIUM PHOSPHATE ESTER

Abstract: Described is a stable pharmaceutical composition of 3-(hydroxymethyl)-5,5-diphenylhydantoin disodium phosphate ester, the produg of 5,5-diphenylhydantoin (phenytoin) a commonly used drug for the treatment and management of epilepsy and other types of convulsive states. It has been found that degradation of the produg to phenytoin can be controlled by controlling the pH of the composition. Controlling the pH to between 8.3 to 9.4 results in the production of diphenylglycinamide as the primary degradant and minimization of degradation to phenytoin. If the pH is maintained at a lower or higher value, then the degradation pattern changes, with earlier than expected product failure.

Description: TITLE STABLE PHARMACEUTICAL COMPOSITION OF 3-(HY0R0XVMETHYL)-5.5- DIPHENYLHYDANTOIN D1S0DIUM PHOSPHATE ESTER BACKGROUND OF THE INVENTION 5,5-D1phenylhydanto1n, phenytoin, is a commonly used drug for the treatment and management of epilepsy and other types of convulsive states. While phenytoin 1s widely used for the treatment of these conditions, it has an extremely low solubility and, consequently, low bloavallability. Phenytoin is a high melting, weakly acidic drug exhibiting poor solubility in water. These properties lead to erratic absorption after oral dosing with both the free acid and the sodium sal . See the papers by S. A. Varia et al., Journal of Pharmaceutical Sciences 73(8): 1068-1090, August 1984. For parenteral use, sodium phenytoin 1s formulated In an aqueous alkaline medium of pH 12 containing 40% propylene glycol and 10% ethanol. The parenteral dosage form can be painful if the Intravenous injection is rapid and the free add appears to precipitate at intramuscular Injection sites. Emergency use of parenteral phenytoin, namely, 1n cases of controlling seizures 1n patients with head Injuries, may require the administration of the drug intramuscularly. To be clinically acceptable, Intramuscular administration of a drug should cause minimal tissue damage at the injection site. Intramuscular administration of sodium phenytoin has been reported to be painful, probably due to the precipitation of phenytoin. It has also been shown to cause hemorrhage, hemato a and necrosis at the Injection site 1n cats and rabbits. Patent 4,260,769 Issued April 7, 1981, and the previously noted articles by S. A. Varia et al. in the Journal of Pharmaceutical Sciences, disclose various prodrugs of phenytoin with more desirable physico- chemical properties. In particular, patent 4,260,769 and the noted publications disclose the phenytoin prodrug 3-(hydroxymethyl)-5,5- dlphenylhydantoln d1sodium phosphate ester which 1s shown to have physlcochemlcal properties that are suitable for a prodrug of phenytoin for parenteral use. S. A. Varia and V. J. Stella, at pages 1087-10901n the Journal of Pharmaceutical Sciences, report that the compound did not exhibit any tissue damage after subcutaneous or intramuscular admiπistratlon and thus, would be a suitable prodrug candidate for intramuscular delivery of phenytoin. However, this prodrug tends to degrade with the subsequent precipitation of phenytoin. Common methods used to delay the precipitation point Involve modifying the formulation to contain agents that might solub11i2β larger quantities of the degradation product. These agents include alcohol, propylene glycol, L- arginine, sodium desoxycholate, polysorbate-80, and various combinations of these compounds. SUMMARY OF THE INVENTION It has been found that the prodrug, 3-(hydroxymetby1)-5,5- diphenylhydantoin d1sodium phosphate ester, 1s stable 1n an aqueous system when maintained at a pH αf about 8.3 to 9.4 to produce dlphenylglyclπaride as the primary degradant with minimal quantities of phenytoin. A preferred pharmaceutical composition would contain 35 to 130 mg/mL of the prodrug and 0.05 to 0.2 M buffer. DETAILED DESCRIPTION OF THE INVENTION The stability of the prodrug has always been limited by the occurrence of precipitation in the product. This precipitation has been related to the degradation of prodrug to phenytoin and the subsequent precipitation of phenytoin. A preferred pharmaceutical composition would contain: prodrug: 35 to 180 mg/mL alcohol: USP 0 to 25% propylene glycol: 0 to 25% L-arg1n1ne: 0 to 0,2 M sodium desoxycholate: 0 to 0.1 M ρolysorbate-80: 0 to 1.5% tromethamlne: 0.05 to 0.2 M In water for Injection with the pH adjusted from 8 to 10 with hydrochloric acid or sodium hydroxide. The pH range found to provide the greatest stability is a pH of about 8.3 to 9.4. In this pH range, the choice of buffers is limited, namely, to buffers effective to maintain a pH of about 8 to 10. In addition to tromethamlne, tr1s-(hydroxymethyl)am1nomethanej other buffers which can be used are biclne, N-N-b1s(2-hydroxyethyl)-2-aminoethane- sulfonlc add; trldne, N-{tr1s(hydroxymethyl)methyl]glyc1ne; sodium bicarbonate; glycylglydne; Hepes, N-2-hydroxyethy1p1pera2lne- N'-2-ethanesulfon1c a d; Hepps, N-2-hydroxyethylpiperaz1ne-N'3~propane- sulfonlc add; sodium phosphate; and Taps, 3[[tr1s(hydroxymethyl)me ' thyll- aminojpropanesulfonlc add. Tromethamlne, bldne or tricine are preferred. Suitable wetting agents in addition to polysorbate-80 are: polyoxamer 188 and polyoxyethylene fatty add esters. A more specific composition would be 75 mg/mL prodrug; 0.1 M tromethamlne and a pH of about 8.3 to 9. The following tables Illustrate the stability of a composition of the phenytoin prodrug comprising 75.7 mg/mL prodrug, 0.1 M tromethamlne, pH adjusted to 9.1 with HC1. TABLE I MASS BALANCE OF FORNALDEHYOE IN DEGRADED PRODRUG AGE INITIAL CURRENT PERCENT AS PROORUG PERCENT LOT (HO) TEMP PH POTENCY POTENCY OIZ FORM RECOVERY 2131 27 RT 8.9 98.22 93.75 0.196 5.553 101.30 2140 27 RT 8.9 96.42 92.13 0.172 5.042 100.96 2183 24 RT 8.8 98.06 94.30 0.130 4.450 100.84 2163 24 RT 8.8 98.06 94.30 0.135 4.314 100.70 2211 23 RT 8.3 104.52 103.38 0.033 1.509 100.38 2224 23 RT 8.9 103.75 97.24 0.155 4.349 98.07 2293 16 RT 8.5 100.91 99.11 0.055 1.747 100.00 2295 16 RT 8.3 101.49 99.04 0.040 1.303 98.91 2327 9 40 8.9 100.42 93.74 0.382 7.893 101.59 .2327 β 40 8.9 101.41 94.88 0.342 7.450 101.24 2358 T 40 8.9 98.70 94.34 0.251 6.653 102.58 2360 7 40 8.9 99.63 94.61 0.246 5.364 100.59 OIZ - 5,5-DIPHENYL-4- MIMZOLIDIHONE FORM - FORHALOEHVDE TABLE II HASS BALANCE OF THE 75 HG/HL PHENYTOIN PRODRUG USING H€THOO I AGE INITIAL DEGRADATION PRODUCTS (PERCENT AS PRODRUG) PERCENT r (HO) TEMP PH POTENCY POTENCY PHEH DPG BZP Ml UHKβ PORN RECOVERY !l 27 RT θ.8 98.22 93.75 0.211 0.295 0.001 0.196 5.046 5.553 101.30 JO 27 RT 8.8 96.42 92.13 0.189 0.245 0.004 0.172 4.604 5.042 100.96 13 24 RT 8.8 98.06 94.30 0.131 0.053 0.002 0.130 4.264 4.450 100.84 13 24 RT 8.8 98.06 95.57 0.13D 0.049 O.0O3 0.135 4.132 4.314 102.00 11 23 RT 8.3 104.52 103.38 1.016 0.011 0.0003 D.033 0.482 1.509 100.38 !4 23 RT 8.9 103.75 97.24 0.106 0.047 0.0015 0.155 4.195 4.349 98.07 J3 16 RT 8.5 100.91 99.11 0.053 0.000 0.0005 0.055 1.694 1.747 100.00 )5 16 RT 8.3 101.49 99.04 0.059 0.000 0.0006 0.040 1.243 1.303 98-91 n 9 40 8.8 100.42 93.74 1.485 1.147 0.013 0.382 5.248 7-893 101.59 n 8 40 8.8 101.41 94.88 1.071 0.746 0.014 0.342 5.619 7.450 101.24 .a 7 40 8.8 98.70 94.34 0.769 0.404 0.006 0.251 5.474 6.653 102.58 30 7 40 8.8 99.63 94.61 0.800 0.419 0.005 0.246 4.140 5-364 100.59 AVERAGE RECOVERY 100.71 PHENYTOIN DIPHENYLGLYCINE BENZOPHENQNE 7 » 5 r 5-01PHEMU-4-tniOAZOL10INOKE <B* « UNKNOWN 8, CALCULATED AS FOLLOWS: U KB - FORH - PHEW - DPG - BZP 3M - FORMALDEHYDE TE: Unknown B (UN KB) has been identified as diphenylglycinuide TABLE HI NEW HASS BALANCE OF 75 HG/HL PROORUG USING HETHOO II 9653 DEGRADATION PROOUCTS AGE PERCENT (PERCENT AS PROORUG) PERCENT LOT (HO) TEHP PN OF INITIAL PHEN DPG OIZ DPGA RECOVERY 2131 30 RT 8.8 93.06 0.141 0.243 0.174 5.144 98.76 2140 30 RT 8.8 94.79 0.148 0.247 0.182 5.240 100.61 21B3 27 RT 8.8 98.40 ND 0.116 0.137 3.021 101.67 2211 25 RT 8.3 98.64 0.097 0.041 0.027 1.254 100.06 2224 24 RT 8.8 94.85 0.104 0.110 0.163 3.810 99-04 2293 18 RT 8.5 98.70 ND 0.080 ND 1.631 100.41 2295 18 RT 6.3 98.53 ND 0.032 0.034 1.163 99.76 2327 10 40 8.8 92.11 1.491 1.224 0.437 5.068 100.33 2356 9 40 8.8 93.21 1.110 0.757 0.329 4.153 99.56 2360 9 40 8.8 92.34 1.157 0.766 0.323 4.115 98.70 AVERAGE RECOVERY 99.89 PHEN - PHENYTOIN DPG - DIPHENYLGLYCINE DIZ ■ 5.5-DJPHENYL-4-IHIMZ0LIDIN0NE DPGA - OIPNENYLGLYCINAHIDE (UNKB in Table II) NO - NOME DETECTEO Initially, it was proposed that phenytoin prodrug decomposed via a simple two-step pathway resulting in phenytoin. However, it has been determined that phenytoin is not the only decomposition product and could only account for a small portion of the degraded prodrug. The degradation pathway has been determined to proceed from phenytoin prodrug to formaldehyde, 5,5-d1phenyl-4-1m1da2olidinone (DIZ), dlphenylglycin- amlde, diphenylglydne, benzophenone, and phenytoin via the pathways described. Overall Degradation Pathway(s) The overall degradation pathway is shown in Scheme V. Many of the steps involved include consumption of hydroxyl, Indicating that the pH of the formulated product should decrease with time. This has been observed in the routine stability program for this product. The addition of a buffer to prevent the pH from dropping significantly from its initial value over the lifetime of the product 1s required. Small changes in the degradation pathway occur as the pH drops. It 1s seen that as the pH drops the rate of phenytoin formation increases and the rate of DIZ formation decreases. This Indicates that the proposed hydantoln ring opening by the phosphate appears to be the rate limiting step in the primary degradation pathway of, phenytoin prodrug. However, formation of phenytoin increases and the solubility of phenytoin decreases as the pH is lowered thus, diminishing the shelf-life of the product due to the saturation of the aqueous solution and eventual precipitation of phenytoin. The chosen pH of the finished product allows the degradation to proceed such that the primary degradant is dlphenyl- glydnamlde, while minimal quantities of phenytoin are produced and shelf-Hfe 1s maximized. Mass Balance Determination Several samples at room temperature and 40*C were analyzed to determine mass balance. Analysis of phenytoin prodrug potency, formaldehyde, 2,2-dlpheπylglydne, 5,5-d1phenylhydantoiπ, 5,5-diphenyl- 4-1midazol1d1none and benzophenone concentrations were performed using the gradient HPLC method. Analysis of phenytoin prodrug potency, 2,2- dlphenylglydne, 2,2-d1phenylglyc1namide (as 2,2-diphenylglydπe), 5,5- di henylhydantoin, and 5,5-d1phenyl-4-imidazolid1none concentrations were determined using the isocratic HPLC method. Molar equivalents were calculated and mass balance results were determined and compared. Hethod Statistics and Comparison Method I - Gradient Method Several standard curves of each compound were chromatographed for the determination of method linearity. The peak areas and heights were plotted versus respective concentrations to yield calibration curves. A11 standard curves typically had a correlation coefficient of >0,99. Standard peak heights or areas were shown to be within 4% of the linear regression line thereby passing pre-established system suitability requirements. Replicate Injections of a standard solution of each compound were chromatographed. Relative standard deviations were less than 1.7% using peak areas and less than 2.2% using peak heights. These results confirm the method 1s precise. The same dilutions of standards were used for determination of limit of detection and limit of quantltatlon. All standards were chromatographed. Peak areas were measured by the data system and linearity was confirmed. Data from standard curve injections before and after a set of sample injections were collected to determine the suitability and effectiveness of the HPLC system. Limits of quantltatlon were experimentally determined and are shown below. Peak Area Peak Height Dlphenylglyclπe 8.3 μg/mL 27.7 μg/mL Diphenylhydantoin 0.5 μg/mL 3.0 μg/mL D1pheny1-4-1nt1dazol1d1none 8.9 μg/mL 1.5 μ/mL Benzophenone 0.05 μg/mL 0.05 μg/mL Llwlts of detection were experimentally determined and are shown below. Peak Area or Height Diphenylglyclne 1.0 μg/mL Diphenylhydantoin 0.3 μg/mL D1pheny1-4-1m1dazol1d1none 0.5 μg/mL Benzophenone 0.01 μg/mL A combination standard curve containing 2,2-dlphenylglycine, 5,5-d1phenylhydantoin and 5,5-dipheπyl-4-1midazolid1none was chromatographed several times for the determination of equality with Individual standard curves. The peak areas and heights were plotted versus respective concentrations to yield calibration curves. Slopes and y-1ntercepts were compared to individual standards, confirming their equality. Replicate injections of a combination standard solution were chromatographed. Relative standard deviations were less than 1.7% using peak areas and less than 2.0% using peak heights with the exception of dlphenylglydne, which was 3.09% using peak heights. This confirms the method 1s precise using the combination standard curve. Mass Balance Several samples kept at various lengths of time at room temperature and 40'C were analyzed to determine mass balance. Initial and current potency, along with current formaldehyde concentration data, were used to determine mass balance. Dlphenylglydne, diphenylhydantoin, d1phenyl-4-imidazol1dinone and benzophenone concentrations were chromatographlcally determined using Method I. From this data, mass balance was calculated. Initial and current potency values were converted to Initial and current moles of phenytoin prodrug. Formalde¬ hyde, dlphenylglydne, diphenylhydantoin, d1phenyl-4-1m1dazol1d1πone and benzophenone concentrations were converted to molar equivalents. Using the value of moles of formaldehyde, diphenylglydne, diphenylhydantoin and benzophenone, the moles of Unknown B (which later was determined to be diphenylglydnaiilde) were calculated using Equation 1. Unknown B - Formaldehyde (moles) - dlphenylglydne (moles) (1) Moles* diphenylhydantoin (moles) - benzophenone (moles) Moles * Current moles + Unknown B (moles)* + dlphenylglydne (2) Determined (moles) + diphenylhydantoin (moles) + d1pheny1-4- 1m1dazo11d1none (moles) + benzophenone (moles) % of Initial * Holes Determined x 100 (3) Recovered Initial Moles * Unknown B was determined to be diphenylglydnamlde The percent recovery of 12 samples analyzed was 98.0 to 102.6% thereby proving mass balance (Table I). Method II - Isocratlc Method Linearity Standard curves were prepared and injected to determine the linearity of the Isocratlc method. In each case linear regression lines for dlphenylglydne, 5 t 5-d1phenyl-4-1m1dazol1d1none and phenytoin had correlation coefficients of greater than 0.999. Diphenylglycinamide was identified as a compound of degradation, previously referred to as Unknown B. As no standard for diphenylglycinamide is available, the curve for dlphenylglydne was used to determine the concentrations of the samples. Precision of the Isocratlc method was performed only by analysis of several lots of degraded prodrug and comparing the results to the results of the gradient method (see Tables II and III). The results showed very favorable comparisons for all the degradants. The major difference 1s seen In the diphenylglycinamide (previously referred to as Unknown B) levels. As 1t was quantitated using dlphenylglydne as a standard rather than by difference (Equation 1), a slight decrease was observed. These results indicate that quantltatlon by difference 1s only affected by the variation in the formaldehyde assay. SCHEME V

Claims: hat is Claimed Is; 1. An Injectable, aqueous pharmaceutical composition for the treatment and management of convulsive states comprising an effective amount of 3-(hydroxymethyl)-5,5-diphenylhydaπtoin disodlum phosphate ester (phenytoin prodrug) for treating such convulsive states, said composition comprising about 35 mg to about 180 mg of prodrug/mL of solution and 0.05 to 0.2 M buffer; said composition having a pH range of about 8.3 to 9.4, the prodrug degrading 1n aqueous solution to produce diphenylglycinamide as the primary degradant with minimal quantities of phenytoin, the pH range of said composition acting to allow the degradation to proceed whereby the shelf-life of the prodrug in an aqueous composition is maximized. 2. The composition of Claim 1 wherein the buffer is selected from the group comprising tromethamlne, bidne and tricine. 3. The composition of Claim 2 wherein the buffer 1s tromethamlne. 4. The composition of Claim 3 wherein the prodrug 1s present 1n the amount of 75 mg/mL. 5. The composition of Claim 1 wherein the pH is about 8.3 to 9. 6. A method for the treatment or management of a convulsive state in a mammal comprising administering by subcutaneous or intramuscular administration to a mammal in need of such treatment an aπtl-convulsive amount of a stable, pharmaceutical composition of the prodrug 3-(hydroxymethyl)-5,5-d1phenylhydaπto1n disodlum phosphate ester, said composition comprising from about 35 to 130 mg/mL of prodrug, and from about 0.05 to 2 M of a buffer effective to maintain a pH of about 8.3 to 9.4.

Inventors: HERBRANSON DALE E, ROSENBERG LEONARD S, SPEICHER EARL R, HERBRANSON, DALE, E., ROSENBERG, LEONARD, S., SPEICHER, EARL, R.
Applicants: DU PONT, E.I. DU PONT DE NEMOURS AND COMPANY
Application year: 1990
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K47, A61P25, A61P43