Quality Evaluation of Carbamazepine Formulations: A Comparative Study

Correspondence A A Araújo Departamento de Biofísica e Farmacologia Centro de Biociências Universidade Federal do Rio Grande do Norte Av Senador Salgado Filho SN Lagoa Nova 59078900 Natal RN Brasil Email aurigenaufrnetbr Article Brazilian Journal of Pharmaceutical Sciences vol 46 n 3 julset 2010 Determination of carbamazepine in pharmaceutical formulations Lílian Grace da Silva Solon¹ Ana Isabel Maia de Oliveira¹ Gerlane Coelho Bernardo Guerra 12 Luiz Alberto Lira Soares 13 Aurigena Antunes de Araújo 12 ¹Department of Pharmacy Federal University of Rio Grande do Norte 2Department of Biophysics and Pharmacology Federal University of Rio Grande do Norte 3Department of Pharmaceutical Sciences Federal University of Pernambuco The aim of this study was to evaluate the quality of five different solid formulations of carbamazepine The reference formulation was Tegretol 20000 mg Novartis and the others were generic formulation of carbamazepine 20000 mg National Industry similar formulation of carbamazepine 20000 mg National Industry and two formulations of carbamazepine 20000 mg acquired from two different compounding pharmacies The latter consisted of capsules obtained in Natal the capital city of the Brazilian State of Rio Grande do Norte The quality of samples was evaluated through physical and physicalchemical tests including weight diameter thickness content dissolution disintegration hardness friability and moisture The results of friability analysis showed that all formulations met Brazilian and United States Pharmacopeia USP specifications In spite of having a higher hardness compared to the reference the generic formulation had a lower disintegration time This could be associated to the presence of crospovidone in its formulation Results of this study showed that all formulations had dissolutions which were in accordance with Brazilian Pharmacopoeia specifications and quality control tests An exception was found for the similar formulation which had a hardness parameter that exceeded the USP standard However this difference was not significant given the similar formulations satisfactory disintegration time Uniterms Carbamazepine Medicinesquality control Generic medicines Similar medicines Medicines magistral formulation O objetivo desse trabalho foi avaliar a qualidade de cinco formulações de carbamazepina na dosagem de 20000 mg medicamento referência Tegretol Novartis medicamento genérico indústria nacional medicamento similar indústria nacional e cápsulas do mesmo medicamento obtidas de duas farmácias de manipulação da cidade do Natal RN Os ensaios realizados foram peso médio diâmetro espessura teor dissolução desintegração dureza friabilidade e umidade Foi observado que nenhuma das amostras analisadas apresentou friabilidade superior ao limite máximo determinado pela Farmacopéia Americana 15 O medicamento genérico apesar de apresentar dureza superior em relação ao medicamento de referência desintegrou em menor tempo o que pode estar relacionado à crospovidona presente na formulação As amostras analisadas atenderam às especificações da Farmacopéia Brasileira no que diz respeito à dissolução Em geral os resultados das amostras A B C D e E foram considerados satisfatórios uma vez que atenderam as especificações farmacopéicas Embora a apresentação similar não tenha atendido ao padrão USP no que diz respeito à dureza esse dado não se mostrou significativo uma vez que o tempo de desintegração foi satisfatório Unitermos Carbamazepina Medicamentoscontrole de qualidade Medicamento genérico Medicamentos similares Medicamentosformulação magistral LG da S Solon AIM de Oliveira GCB Guerra LAL Soares AA de Araújo 510 INTRODUCTION The efficacy of carbamazepine efficacy was confirmed in the 1960s when it was launched in the commercial market It was used as an antiepileptic for the first time in the United States in 1974 Carbamazepine was initially prescribed for adult patients and later indicated for use in children Carbamazepine is considered one of the best anticonvulsivant producing less psychological alterations and behavior effects Castro et al 2001 Carbamazepine is used in the treatment of trigeminal and glossopharyngeal nerve neuralgia acting by reducing repetitive activation of the action potential Goodman Gilman 2003 This molecule shows unique pharmacokinetic properties giving it a low solubility in water below 20000 µgmL After oral administration it has a slow rate absorption which requires the use of a relatively large dose Ambrogi et al 2007 Currently several commercial presentations of carbam azepine are available in Brazil Based on their source they can be divided into reference generic similar and those produced in compounding pharmacies According to Brazilian law 9787 published in February 10th of 1999 reference medicines are those commercialized under registration in Brazil Reference medi cines contain the original drug which was rigorously developed and investigated and have been submitted to preclinical and clinical studies for evaluation of their safety and therapeutic efficacy Yacubian 2007 Generic medicines have been in use in the United States and Europe since 1960 They can have a different formulation compared to the reference medicine but must present the same dose route of administration and presentation as the reference Baracho 2008 In addition generics must have the same pharmaceutical equivalence and bioequivalence as the reference medicine This must be attested by the regulatory agency of each country In Brazil this role is performed by the National Health Surveillance Agency ANVISA Storpirtis et al 2004 The bioequivalence guarantees that two presentations will have the same drug absorption rate and quantity and hence bioavailability Yacubian 2007 The similar medicine is the form having the same drug dose pharmaceutical form route of administration dosage and indication as the reference medicine but which has not necessar ily been submitted to equivalence and bioequivalence studies The medicines acquired from compounding pharmacies are normally in capsule form This pharmaceutical form permits a custom dosage of the drug which reduces the cost compared to an industrialized medicine and also facilitates acquisition of the medicine The capsules also provide a means of obtaining a medicine that does not exist in the pharmaceutical market Azevedo Ribeiro Araújo 2008 The aim of this study was to evaluate the physical and physicalchemical quality control of five formulations of carbamazepine namely a generic presentation a similar pre sentation and two presentations acquired from two different compounding pharmacies MATERIALS AND METHODS Materials A carbamazepine standard was acquired from Cristália Laboratory Sao Paulo The methanol used was purchased from Merck Germany and the sodium sulfate lauryl from Cromato Produtos Químicos Ltda São Paulo Two formulations of carbamazepine were acquired from two different compound ing pharmacies in Natal Rio Grande do Norte Brazil Besides these two formulations Tegretol 20000 mg Novartis as the reference medicine a generic formulation of carbamazepine 20000 mg National Industry and a similar formulation of carbamazepine 20000 mg National Industry were also used as shown in Table I Instrumentation The following devices were used in the analysis an analytical balance Ohaus Adventurer model digital caliper Mitutoyo spectrophotometer Varian Carry 50 Cone model dissolutor Erweka DT 80 model disintegrator Digimatic Cali per Varian VK 100 model durometer Varian VK 200 model friabilometer Varian infrared balance Ohaus MB 45 model and an Ultrasonic Unique Cleaner Ultrasound USC 1400 model Methods The five formulations A B C D and E analyzed in this study were submitted to physical and physicalchemical tests These tests were mean weight diameter thickness content dissolution disintegration hardness friability and moisture Mean weight twenty tabletscapsules of each formulation were individually weighed The mean was obtained and the TABLE I Samples of reference generic and similar tablets and magistral capsules of carbamazepine 20000 mg Carbamazepine 20000 mg Sample Reference tablets Novartis A Generic tablets National Industry B Similar tablets National Industry C Capsules Compounding Pharmacy 1 D Capsules Compounding Pharmacy 2 E Determination of carbamazepine in pharmaceutical formulations 511 relative standard deviation RSD could not exceed 75 for tablets and 10 for capsules USP Diameter and Thickness a caliper was used to measure the diameter and thickness of ten tablets of A B and C samples USP Content for this test a stock solution was prepared by dissolving 10 mg of carbamazepine in 100 mL of methanol and then a standard solution containing 10μgmL was obtained from the stock solution A test solution of the five formulations A B C D and E was made at the same concentration of 1000 μgmL of carbamazepine Absorptions of these solutions were determined at 285 nm using methanol as a blank The sample analyzed could not contain less than 92 or more than 108 of carbamazepine Farmacopéia Brasileira 1977 Dissolution the dissolution medium used in this test was distilled water with 1 sodium sulfate lauryl totaling 900 mL Six samples of each formulation were previously weighed and then placed in the dissolutor All samples were submitted to 75 rpm on apparatus II paddle and 37 05ºC temperature for 60 minutes After finishing this step aliquots were collected and analyzed at 285 nm Farmacopéia Brasileira 1977 Disintegration this test was performed according to USPs methodology Six samples of each formulation had to disintegrate in less than 30 minutes USP Hardness this parameter measured the level of force necessary to the break the tablets The test was performed on ten tablets of samples A B and C The results had to lie within a 4 to10 kilopound Kp range USP Friability twenty A B and C samples previously wei ghed tablets were placed in a friabilometer with a preprogram med speed for five minutes After finishing this step samples were reweighed and the difference in tablet weight calculated The samples could not lose more than 15 in weight USP Moisture twenty tabletscapsules were sprayed with 15g pounds and placed in an infrared balance which measured moisture content The samples could not lose more than 5 in weight USP RESULTS AND DISCUSSION Tablet weight is determined by the density of the formu lation components and by its proportions The USP establishes limits for mean weight of noncoated tablets that apply to tablets containing at least 5000 mg of active substance drug compri sing more than50 of weight Tablets which have a mean weight of between 8000 and 25000 mg may have a maximum weight variation of 75 The results of these tests are shown in Table II The dimension and form of tablets are determined by the type of compression tool used Thus this parameter varies with the compressive load applied and must be controlled to adhere to a maximum variation of 5 The mechanical properties of tablets can be quantified by friability and hardness The friability is directly related to the hardness and indicates resistance to abrasion which can occur inside the end packaging or during transport or manipulation This parameter is important in choosing the adequate exci pients to prevent fast disintegration of the tablet and posterior dissolution of the drug before the desired time The maximum loss of weight must not exceed 15 of tablet weight The results of the friability test were 025 054 and 034 for samples A B and C respectively These friability levels met USP specifications Hardness is an important parameter to estimate disintegra tion time since resistant tablets do not disintegrate in the time required to satisfy the dissolution specifications Tablets with lo wer hardness are unable to resist manipulation The force needed to achieve tablet breakage is expressed in kilopounds Kp The values found of between 4 and 10 Kp are considered satisfactory for noncoated tables oral administration The similar presen tation of carbamazepine sample C had a hardness value greater than that determined by the USP Table II However this result TABLE II Results of hardness diameter thickness mean weight disintegration content and moisture tests of 20000 mg carbamazepine tablets and capsules Sample Hardness kP RSD Diameter mm RSD Thickness mm RSD Mean weight mg RSD Disintegration min RSD Content RSD Humidity A 748 134 902 065 370 119 29552 425 030 058 9657 237 230 B 839 087 911 187 489 217 29402 339 025 340 9834 105 200 C 1786 289 1105 354 528 389 47549 126 232 433 10147 198 367 D 26153 355 414 235 9314 035 308 E 30972 728 426 156 9414 113 425 n 10 n 20 n 6 n 3 LG da S Solon AIM de Oliveira GCB Guerra LAL Soares AA de Araújo 512 proved nonsignificant because the disintegration time within the 30minute limit of this formulation was considered satisfactory As expected the tablet with higher hardness presented a longer disintegration time However the generic presentation in spite of having a greater hardness compared to the reference formulation had a shorter disintegration time This fact may be due to use of crospovidone in its formulation This excipient is a super disintegrate a substance that facilitates the disintegra tion process even when used in small quantities Prista Alves Morgado 1995 Absorption is a parameter which depends on both di sintegration and dissolution parameters Previously only the disintegration was required as an indicator of a drugs release parameter However several studies showed that the turbulent agitation provided by apparatus II of the disintegrator contrasts with the smooth and normal agitation of the gastric content du ring the contractions of the stomach In addition these studies revealed that the disintegrated particles do not disperse in the organism but remain aggregated Therefore the disintegration test is now used only to control the variations between each bulk size and should not be used as a bioavailability standard Guyot Hermann 1992 After oral administration the solid forms can disintegrate or dissolve later upon interaction with the gastrointestinal fluid Hence the speed of dissolution controls the accumulation rate of the drug in the blood while its kinetics provide data about the bioavailability of a medicine as well as its therapeutic effects in vivo For this reason this test is gaining more importance in the pharmaceutical industry It is a parameter used to evaluate the quality of a medicine Menegola et al 2007 Table III shows that all presentations analyzed met the USP specifications regarding the dissolution test Dissolution is an important test of quality control and acts as a useful tool to predict bioavailability In some cases it can substitute clinical studies determining bioequivalence The term oral bioavailability is defined as the fraction of the administrated drug which reaches the bloodstream from the gastrointestinal tract Bosso 2008 When an adequate dissolution method is chosen the dis solution rate of the product can be correlated with the absorption rate of the drug in the organism In general a fast dissolution rate results in a fast rate of appearance of the drug in blood plasma Thus correlation between the dissolution rate and absorption rate of the drug can be established Shargel Ayu Andrew 1999 As outlined above the bioavailability of a drug is defined by its absorption speed and extension and is important in determining whether the drug reaches its target site at an effective therapeutic concentration Aulton 2005 Bioavailability can be influenced by the route of administration pharmaceutical form and formulation The route of administration was not relevant in this study because all formulations analyzed used the same route Variability in bioavaila bility exhibited by a drug incorporated in different pharmaceutical forms or in different formulations of the same pharmaceutical form can result in higherthandesired plasmatic concentrations thereby potentiating side effects or in lowerthanrequired levels precluding effective therapeutic action The effective surface area of a drug is an important factor that should be correlated with its speed of dissolution particularly when dealing with low solubility molecules such as carbamazepine When increased effective surface area is ensured the disintegration of a tablet is an important factor for the drugs absorption Should fast release dissolution and consequent absorption be desired then tablets must disintegrate rapidly and completely in gastrointestinal fluids The speed of this process is affected by the compression force applied during tablet production as well as by the concentration and type of drug and excipients diluent disintegrant aggregating lubricant and wetting agent A medicine which fulfils the requirements of the phar macopeia in terms of dissolution tends to indicate safe and satisfactory in vivo release Also concerning the contact surface the bioavailability of a drug administrated in a gelatin capsule can be the same or even better than the bioavailability of a tablet containing the same drug This can be the case because the gelatin capsule dissolves rapidly when in contact with the gastrointestinal fluids and liberates its contents which disperses rapidly and efficiently The ANVISA do not currently have guidelines regulating quality control of similar medicines or drugs produced in com pounding pharmacies From this year pharmaceutical equiva lence tests will be required for these drugs where determination in the laboratory shall verify whether they indeed possess the same characteristics as the reference drug Bioavailability will be assessed only from 2014 Rumel Nishioka Santos 2006 CONCLUSION The quality control studies for the A B C D and E solid formulations of carbamazepine 20000 mg were considered sa TABLE III Results of dissolution test S1 stage of 20000 mg carbamazepine tablets and capsules Sample Maximum dissolution Minimum dissolution Mean RSD A 8115 7450 7784 373 B 9687 9263 9425 170 C 10572 9624 10441 234 D 9610 9074 9410 214 E 10440 9518 9639 442 Determination of carbamazepine in pharmaceutical formulations 513 tisfactory in that they met American and Brazilian Pharmacopeia specifications An exception occurred with the similar presenta tion which did not meet the USP specifications However this result proved irrelevant because the disintegration time of this formulation was considered satisfactory ACKNOWLEDGEMENTS The authors are grateful for the support from the Núcleo de Pesquisa em Alimentos e Medicamentos NUPLAMUFRN PROPESQUFRN and CNPq 47713120077 REFERENCES AMBROGI V PERIOLI L MARMOTTINI F ACCORSI O PAGANO C RICCI M ROSSI C Role of mesoporous silicates on carbamazepine dissolution rate enhancement Micropor Mesopor Mater v113 n13 p445452 2007 AULTON M E Delineamento de formas farmacêuticas 2ed Porto Alegre Artmed 2005 677 p AZEVEDO R C P RIBEIRO G P ARAÚJO M B Desenvolvimento e validação do ensaio de dissolução para captopril em cápsulas magistrais por CLAE Rev Bras Cienc Farm v44 n2 p261269 2008 BARACHO N C V Bioequivalence study of four different trademarks of enalapril maleate in spontaneously hypertensive rats Acta Cir Brás v23 n2 p173178 2008 BOSSO S T ENZWEILER J Ensaios para determinar a bio disponibilidade de chumbo em solos contaminados revisão Quim Nova v31 n2 p394400 2008 BRASIL Ministério da Saúde Lei nº 9787 de 10 de fevereiro de 1999 Diário Oficial da União Brasília de 1999 Seção1 p1 CASTRO A P B M REDMERSHI M G PASTORINO A C PAZ J A FOMIN A B F JACOB C M A Secondary hypogammaglobilinemia after use of Carbamazepine case report and review Rev HospClín Fac Med S Paulo São Paulo v56 n6 p189192 2001 FARMACOPÉIA BRASILEIRA 3ed São Paulo Andrei Editora 1977 p181 GOODMAN L S GILMAM G A As bases farmacológicas da terapêutica 11ed Rio de janeiro Mc Graw Hill 2007 1821 p GUYOTHERMANN AM The disintegration and disintegrating agent STP Pharma Sci v2 n6 p445 462 1992 MENEGOLA J STEPPE M SCHAPOVAL E E S Dissolution test for citalopram in tablets and comparison of in vitro dissolution profiles Eur J Pharm Biopharm v67 p524530 2007 PRISTA L N ALVES A C MORGADO R Tecnologia farmacêutica 4ed Lisboa Fundação Calouste Gulbenkian 1996 2257 p RUMEL D NISHIOKA S A SANTOS A A M Intercambialidade de medicamentos abordagem clínica e o ponto de vista do consumidor Rev Saúde Pública v40 n5 p921927 2006 SHARGEL L AYU ANDREW B C Applied biopharmaceutics and pharmacokinetics 4ed New York McGraw Hill 1999 768 p STORPIRTIS S MARCOLONGO R GASPAROTTO FS VILANOVA CM Equivalência farmacêutica no contexto da intercambialidade entre medicamentos genéricos e de referência bases técnicas e científicas Infarma Brasília v16 n910 p5156 2004 YACUBIAN E M T Medicamentos genéricos no tratamento das epilepsias uma reflexão J Epilepsy Clin Neurophysiol v13 n3 p127130 2007 UNITED STATES PHARMACOPEA 30ed NF 25 Rockville USP Convention 2007 2751 p Received for publication on 04th June 2009 Accepted for publication on 26th January 2010