Equilibrium solubility versus intrinsic dissolution: characterization of lamivudine, stavudine and zidovudine for BCS classification

Abstract

Solubility and dissolution rate of drugs are of major importance in pre-formulation studies of pharmaceutical dosage forms. The solubility improvement allows the drugs to be potential biowaiver candidates and may be a good way to develop more dose-efficient formulations. Solubility behaviour of lamivudine, stavudine and zidovudine in individual solvents (under pH range of 1.2 to 7.5) was studied by equilibrium solubility and intrinsic dissolution methods. In solubility study by equilibrium method (shake-flask technique), known amounts of drug were added in each media until to reach saturation and the mixture was subjected to agitation of 150 rpm for 72 hours at 37 °C. In intrinsic dissolution test, known amount of each drug was compressed in the matrix of Wood's apparatus and subjected to dissolution in each media with agitation of 50 rpm at 37 °C. In solubility by equilibrium method, lamivudine and zidovudine can be considered as highly soluble drugs. Although stavudine present high solubility in pH 4.5, 6.8, 7.5 and water, the solubility determination in pH 1.2 was not possible due stability problems. Regarding to intrinsic dissolution, lamivudine and stavudine present high speed of dissolution. Considering a boundary value presented by Yu and colleagues (2004), all drugs studied present high solubility characteristics in intrinsic dissolution method. Based on the obtained results, intrinsic dissolution seems to be superior for solubility studies as an alternative method for biopharmaceutical classification purposes.Uniterms: Drugs/solubility. Drugs/dissolution rate. Intrinsic dissolution/method/biopharmaceutical classification. Biopharmaceutical Classification System.A solubilidade e a taxa de dissolução de fármacos são de grande importância em estudos de pré-formulação de formas farmacêuticas. A melhora na solubilidade permite que os fármacos sejam candidatos potenciais à bioisenção, podendo ser uma boa maneira para desenvolver formulações dose-eficientes. O comportamento de solubilidade da lamivudina, estavudina e zidovudina em solventes individuais (sob faixa de pH 1,2 a 7,5) foi estudado pelos métodos de solubilidade em equilíbrio e dissolução intrínseca. No estudo de solubilidade pelo método do equilíbrio (método de agitação de frascos), conhecidas quantidades do fármaco foram adicionadas em cada meio até atingirem a saturação e a mistura foi submetida à agitação de 150 rpm por 72 horas a 37 °C. No ensaio de dissolução intrínseca, conhecida quantidade de cada fármaco foi comprimida na matriz do aparato de Wood e submetida à dissolução em cada meio com agitação de 50 rpm a 37 °C. No método de solubilidade em equilíbrio, a lamivudina e a zidovudina podem ser consideradas como fármacos altamente solúveis. Embora a estavudina apresente alta solubilidade nos meios pH 4,5, 6,8, 7,5 e água, a determinação da solubilidade em pH 1,2 não foi possível devido a problemas de estabilidade. Com relação à dissolução intrínseca, a lamivudina e a estavudina apresentaram alta velocidade de dissolução. Considerando o valor ...

Solubility evaluation of didanosine: a comparison between the equilibrium method and intrinsic dissolution for biopharmaceutics classification purposes

“…The amount of drug was sufficient for media supersaturating, which was characterized by an insoluble amount of drug in the bottom of each flask. The samples were kept in an incubator shaker at 37.0±0.5 ºC and orbital agitation of 150 rpm (rotations per minute) for 72h (Dezani et al, 2013a;Okumu, Dimaso, Lobenberg, 2009).…”

“…For immediate-release oral dosage forms, rates of dissolution are constantly discussed since the publication of the guidance for industry by the FDA (Food and Drug Administration). Thus, when in combination with the dissolution, the BCS takes into consideration three major factors guiding the rate and extent of drug absorption from immediate release solid oral dosage forms: dissolution rate, solubility and permeability (Amidon et al, 1995;FDA, 2000;Dezani et al, 2013a).…”

“…The compression force should be sufficient to form the drug disk (die), which remains stable until its complete dissolution in the media throughout the experiment time. The intrinsic dissolution method is not influenced by the compression force, dissolution volume, distance of the drug disk from the bottom of the dissolution vessel or the drug disk rotation speed (Dezani et al, 2013a;Wood, Syarto, Letterman, 1965;Yu et al, 2004;Zakeri-Milani et al, 2009).…”

“…In this case, discrepancies may be observed in a comparison between solubility and intrinsic dissolution methods. Thus, the intrinsic dissolution does not take into consideration the dose effect (Dezani et al, 2013a;Yu et al, 2004).…”

“…Based on that, new drugs can have characteristics defined for solubility using the intrinsic dissolution. Besides, as dose strength may vary from country to coumtry due regulatory matters, the intrinsic dissolution method might be used as a universal tool for solubility characterization (Dezani et al, 2013a;Yu et al, 2004;Zakeri-Milani et al, 2009).…”