CC BY
11PHARMACEUTICS
STUDY IN VITRO KINETICS OF DISSOLUTION POORLY WATER SOLUBLE APIS FOR PREDICTING A TECHNOLOGY OF SOLID DOSAGE FORMS
Shchykovskyi O.
Postgraduate student, National University of Pharmacy, Kharkiv, Ukraine
Krutskikh T.
Doctor of Pharmacy Sciences, Professor National University of Pharmacy, Kharkiv, Ukraine
Abstract
The important characteristic for predicting a bioavailability of poorly water-soluble APIs from solid dosage forms are in vitro kinetics of dissolution of APIs in physiologically similar mediums. The study of in vitro kinetics during research and development of formulation solid dosage forms makes it possible to predict a technology of solid dosage forms, which can ensure the necessary bioavailability for poorly water-soluble APIs.
Keywords: riluzole, nimodipine, generic drug, tablets, Rilutek, Nimotop, excipients.
Introduction. Research and development of solid dosage forms containing APIs which are poorly soluble in water to deserve special attention, because the formulation and technology of such drugs directly affects the ability to rate of release a pharmaceutical substance in the human body and as a result of their bioavailabil-ity. On the way of getting APIs into the systemic circulation from oral solid drugs following main stages are distinguished:
• disintegration of solid dosage form upon its entry into the gastrointestinal tract and release of pharmaceutical substance;
• dissolution of pharmaceutical substance in the physiological environment of gastrointestinal tract;
• absorption of pharmaceutical substance from the gastrointestinal tract to systemic circulation through biological membranes.
In accordance with these main stages, it can be argued that the bioavailability of oral drugs that contain poorly water-soluble APIs, in the first place will depend on the solubility of pharmaceutical substances in the physiological environment of gastrointestinal tract, and secondly - from its permeability through biological membranes. Therefore, during research and development of solid dosage forms necessary to conduct a scientific search for the optimal formulation and technology by assessing the rate of dissolution of poorly water-soluble APIs from tablets in physiologically similar mediums using in vitro tests. During in vitro studies to evaluation of dissolution rate from immediate release solid dosage forms in physiologically similar mediums can be performed as follows:
1) if at the stage of disintegration a solid dosage form the dissolution rate is limited, the release rate of pharmaceutical substance can be considered disintegration-controlled, therefore physicochemical property of excipients and pharmaceutical substance included in the drug can have the greatest impact on the release pharmaceutical substance from a solid dosage form;
2) if at the stage of dissolution a solid dosage form the dissolution rate is limited, the release rate of pharmaceutical substance from tablets are controlled by the process of solubilization of pharmaceutical substance particles. Therefore, physicochemical properties of pharmaceutical substance such as chemical form (for example salt, free acid, free base), physical form (for example amorphous or polymorphic substance), primary particle size, solubility in water and others will played a key role. In this case for production of solid drugs will better to use modern technological methods of physical modification of poorly water-soluble APIs, which allow without changing the chemical structure of the active substance to achieve significant improvement of its solubility and bioavailability. These are methods such as reduction of particle size, solid dispersion in soluble carriers, obtaining a solid dispersion using an organic solvent, formation of complexes with cyclodextrins and etc [1, 2, 3].
The aim of this work is evaluation the rate of dissolution of poorly water-soluble substances riluzole and nimodipine from tablets of original drugs "Rilutek" and "Nimotop" during in vitro kinetics studies and forecasting the technology of production of generic drugs for ensure the required bioavailability.
Materials and methods. The objects of the study are poorly water-soluble substances riluzole and nimodipine, as well as the original drugs "Rilutek" and "Nimotop". Pharmaceutical substances riluzole and ni-modipine have moderate and pronounced lipophilic properties, which allow these medicinal substances to penetrate well enough through biological membranes into the systemic circulation, easily bind to plasma proteins, which provides their highly effective therapeutic effect on the human body. According to the biopharma-ceutical classification system of the substance riluzole and nimodipine belong to the II class of BSC, therefore have low solubility and high bioavailability [5]. The in vitro dissolution kinetics of substances riluzole and ni-modipine were studied from tablets of original drugs Rilutek 50 mg film-coated tablets and Nimotop 30 mg film-coated tablets.
Study of in vitro kinetics of dissolution riluzole and nimodipine from tablets of the original drugs "Ri-lutek" and "Nimotop" were performed in three dissolution media, which are recommended by regulators as similar to physiological - phosphate buffer solution (pH 6,8), acetate buffer solution (pH 4,5) and 0,1 M hydrochloric acid solution (pH 1,2). Researches were performed by the "Dissolution" test in accordance with the
requirements of the pharmacopoeia using devices with basket and paddle respectively. Assay of substances riluzole and nimodipine were determined by spectro-photometric method [6].
Results and discussion. At the figure 1 presents results of study in vitro kinetics of dissolution substance riluzole from «Rilutek» tablets in three dissolution media of pH 1.2, 4.5, and 6.8.
Time, min.
Fig. 1. Results of study in vitro kinetics of dissolution substance riluzole from tablets of original drug «Rilutek»
The dissolution kinetic of substance riluzole from tablets "Rilutek" in a medium of 0.1 M hydrochloric acid solution (pH 1.2) is more than 85% in 15 minutes, in a medium of acetate buffer solution (pH 4.5) and phosphate buffer solution (pH 6.8) - approximately 85% in 30 minutes. Such dissolution kinetic of the substance riluzole can be characterized as rapidly soluble or disintegration-controlled, therefore excipients included in formulation may have a significant effect on dissolution of the active substance
from tablets. Consequently, it is advisable to anticipate that for development of a generic drug with the substance riluzole, choice of excipients and their amounts may play a crucial role in achieving bioequivalence with the original drug "Rilutek".
At the figure 2 presents results of study in vitro kinetics of dissolution substance nimodipine from «Nimotop» tablets in three dissolution media of pH 1.2, 4.5, and 6.8.
Time, min.
Fig. 2. Results of study in vitro kinetics of dissolution a substance nimodipine from tablets of original drug
«Nimotop»
The dissolution kinetics of a substance nimodipine from tablets «Nimotop» show that the release rate of nimodipine in dissolution media such as phosphate buffer (pH 6.8), acetate buffer (pH 4.5) and 0.1 M solution hydrochloric acid (pH 1.2) are less than 85% in 30 minutes. Such dissolution kinetics of a substance nimodipine can be characterized as slow or dissolved control. Therefore, dissolution of the active substance
from the tablet is controlled by the process of solubilization of substance particles, namely physicochemical properties of the substance (physical form, solubility, lipophilicity, etc.) determine the process of release rate of the active substance in medium of physiological dissolution. In this case, for improving a solubility of poorly water-soluble substance nimodipine from tablets is better to use
technological methods of physical modification of substance, which will allow without changing a chemical structure of the active substance to significantly improve its solubility in a physiological mediums of gastrointestinal tract.
Conclusions. Based on evaluation in vitro kinetics of dissolution substances riluzole and nimodipine from original drugs "Rilutek" and "Nimotop" were predicted that the improvement of the release rate of the substance riluzole from generic tablets should be carried out at the expense of excipients, and the improvement of the release rate of nimodipine from generic tablets should be carried out at physical modification of active substance.
REFERENCES:
1. Gowthamarajan K., Sachin K. Dissolution Testing for poorly soluble drugs: A Continuing Perspective / K. Gowthamarajan, K. Sachin // Dissolution Technologies.- August 2010.-P. 24 - 32.
2. Rong Liu Water-Insoluble Drug Formulation, Second Edition. - AustarPharma, Edison, New Jersey, USA 2008. - 688 c.
3. Yihong Qiu, Yisheng Chen, Geofl Zhang and other. Developing solid oral dosage forms pharmaceutical theory and practice / Academic Press, 1 edition 2009. - 978 p.
4. Yohei Kawabata, Koichi Wada, Manabu Nakatani, Shizuo Yamada, Satomi Onoue. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: Basic approaches and practical applications. International Journal of Pharmaceutics 420 (2011) 1- 10.
5. DrugBank - база даних лжарських препарапв [Електронний ресурс]. - Режим доступу: субстанщя рилузол -https://www.drugbank.ca/drugs/DB00740 та субстанщя шмодишн -https://www.drugbank.ca/drugs/DB00393.
6. State Pharmacopoeia of Ukraine / State Enterprise, Ukrainian scientific Pharmacopoeia center of medication quality. - 1st ed - Completed 1. -Kharkiv: 2001. - 556 p.
RESERCH OF RAW MATERIAL AND EXTRACTS OF SALIXSACHALINENSIS. F. SCHMIDT
Borodina N.
PhD, Associate Professor of the department ofpharmacognosy, National University of Pharmacy, Ukraine
Kovalyov V.
Dr.hab., Professor, of the department of pharmacognosy, National University of Pharmacy, Ukraine
Koshovyi О.
Dr.hab., Professor, Head of the department ofpharmacognosy, National University of Pharmac, Ukraine
ДОСЛ1ДЖЕННЯ СИРОВИНИ ТА ЕКСТРАКТУ SALIX SACHALINENSIS. F. SCHMIDT
Бородша Н.В.
канд. фарм. наук, доцент кафедри фармакогнозИ, Нацюнальний фармацевтичний ^верситет, Украна
Ковальов В.М.
д-р фарм. наук, професор кафедри фармакогнозИ, Нацюнальний фармацевтичний ymiверситет, Украна
Кошовий О.М.
д-р фарм. наук, професор зав. каф. кафедри фармакогнозИ, Нацюнальний фармацевтичний ymiверситет, Украна
Abstract
Salix sachalinensis. F. Schmidt., family Willow Salicaceae L. - perspective source for obtaining of biological active compounds. The component composition of volatile compounds and organic acids the Salix sachalinensis. F. Schmidt. shoots and extract based on it were investigated using the method of GC / MS. Анотащя
Salix sachalinensis. F. Schmidt., родина Bep6oBi Salicaceae - перспективне джерело отримання приро-дних бюлопчно активних речовин. Методом хромато-мас-спектрометри визначено компонентний склад летких сполук i оргашчних кислот сировини та екстракту Salix sachalinensis. F. Schmidt.
Keywords: Salix sachalinensis. F. Schmidt, GC/MS.
Ключовi слова: Salix sachalinensis. F. Schmidt., хромато-мас-спектрометрiя.
