Inclusion complexes and self-assembled cyclodextrin aggregates for increasing the solubility of benzimidazoles

Albendazole and fenbendazole are imidazole derivatives that exhibit broad spectrum activity against parasites, but the low solubility of these drugs considerably reduces their effectiveness. Complexation of albendazole and fenbendazole with cyclodextrins (ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin) in both water and an aqueous solution of polyvinylpyrrolidone (PVP-k30) was studied to determine if it could increase the solubility and dissolution rate of the drugs. In an aqueous solution, ß-cyclodextrin increased the solubility of albendazole from 0.4188 to ~93.47 µg mL-1 (223×), and of fenbendazole from 0.1054 to 45.56 µg mL-1 (432×); hydroxypropyl-ß-cyclodextrin, on the other hand, increased solubility to ~443.06 µg mL-1 (1058×) for albendazole and ~159.36 µg mL-1 (1512×) for fenbendazole. The combination of hydroxypropyl-ß-cyclodextrin and polyvinylpyrrolidone enabled a solubility increase of 1412× (~591.22 µg mL-1) for albendazole and 1373× (~144.66 µg mL-1) for fenbendazole. The dissolution rate of the drugs was significantly increased in binary and ternary systems, with hydroxypropyl-ß-cyclodextrin proving to be more effective. The presence of the water-soluble PVP-k30 increased the dissolution rate and amorphization of the complexes. Analysis of the changes in displacement and the profile of the cyclodextrin bands in the 1H NMR spectra revealed a molecular interaction and pointed to an effective complexation in the drug/cyclodextrin systems. Monomeric forms and nanoclusters of cyclodextrins were observed in the drug/cyclodextrin systems, suggesting that the increase in solubility of the drugs in the presence of cyclodextrins should not be attributed only to the formation of inclusion complexes, but also to the formation of cyclodextrin aggregates

Assay and physicochemical characterization of the antiparasitic albendazole

The aim of this study was to characterize three batches of albendazole by pharmacopeial and complementary analytical techniques in order to establish more detailed specifications for the development of pharmaceutical forms. The ABZ01, ABZ02, and ABZ03 batches had melting points of 208 ºC, 208 ºC, and 209 ºC, respectively. X-ray diffraction revealed that all three batches showed crystalline behavior and the absence of polymorphism. Scanning electron microscopy showed that all the samples were crystals of different sizes with a strong tendency to aggregate. The samples were insoluble in water (5.07, 4.27, and 4.52 mg mL-1, respectively) and very slightly soluble in 0.1 M HCl (55.10, 56.90, and 61.70 mg mL-1, respectively) and additionally showed purities within the range specified by the Brazilian Pharmacopoeia 5th edition (F. Bras. V; 98% to 102%). The pharmacopeial assay method was not reproducible and some changes were necessary. The method was validated and showed to be selective, specific, linear, robust, precise, and accurate. From this characterization, we concluded that pharmacopeial techniques alone are not able to detect subtle differences in active pharmaceutical ingredients; therefore, the use of other complementary techniques is required to ensure strict quality control in the pharmaceutical industry.

O objetivo do trabalho foi caracterizar três lotes de albendazol com técnicas analíticas farmacopéicas e complementares a fim de estabelecer especificações mais detalhadas para o desenvolvimento de formas farmacêuticas. Os lotes ABZ01, ABZ02 e ABZ03 apresentaram fusão em 208 ºC, 208 ºC e 209 ºC. Foi possível evidenciar, por difração de raios X, que os três lotes apresentaram comportamento cristalino e ausência de polimorfismo. Através da microscopia eletrônica de varredura verificou-se que todas as amostras apresentaram cristais com diferentes tamanhos e forte tendência de agregação. As amostras foram insolúveis em água (5,07; 4,27 e 4,52 µg mL-1) e muito pouco solúveis em HCl 0,1M (55,10; 56,90 e 61,70 µg mL-1) e, ainda, apresentaram pureza dentro da faixa especificada pela F.Bras.V (98% a 102%). O método farmacopéico de doseamento não foi reprodutível, e algumas mudanças foram necessárias. O método foi validado e demonstrou ser seletivo, específico, linear, robusto, preciso e exato. A partir dessa caracterização, pode-se concluir que apenas técnicas farmacopéicas não são capazes de detectar diferenças sutis entre os ingredientes farmacêuticos ativos, necessitando, portanto, de uso de outras técnicas complementares para garantir um rígido controle de qualidade na indústria farmacêutica.

Determination of albendazole as raw material and in tablets by nonaqueous titration with sodium methylate solution

Albendazole is a broad-spectrum benzimidazole anthelmintic recently introduced in the pharmaceutical market. A new volumetric dosage method is proposed, in nonaqueous medium with sodium methylate using DMF as eluent, for albendazole analytical determination as raw material and in tablets. The equivalence point was obtained exactly with the potentiometric method using the second derivative. The method is simple and accurate with a sensitivity limit< '10 POT.-5'M.

Doseamento do albendazol como materia-prima e em comprimidos em meio nao-aquoso com acido perclorico / Albendazole assay (raw material and tablets) by nonaqueous titration with perchloric acid

Albendazol - anti-helmintico benzimidazolico de amplo espectro recentemente introduzido ao mercado terapeutico nacional - foi determinado quantitativamente em meio nao-aquoso, com acido perclorico, tanto como materia-prima, quanto na forma de comprimidos. O ponto final e melhor determinado potenciometricamente

Analise quimico-farmaceutico do albendazol / Pharmaceutical chemistry analyse of albendazole

O albendazol foi analisado por metodos fisicos, fisico-quimicos e quimicos. Comprimidos de duas especialidades contendo albendazol tambem foram analisados por esses metodos. Alem disto a estabilidade termica do farmaco foi observada por diversas tecnicas. Concluiu-se que: 1)O teste de caracterizacao mais indicado e o ponto de fusao ; 2)Das provas de identificacao as mais recomendadas sao: espectrofotometria no infravermelho e no ultravioleta e reacao com acido fosforico originando tiofenol; 3)Dos metodos de determinacao quantitativa, para a materia-prima o mais pratico e o doseamento com acido perclorico e de deteccao potenciometrica do ponto final; espectrofotometria no ultravioleta em meio alcalino ou cromatografia liquida de alta eficiencia sao as tecnicas mais precisas no caso de comprimidos