Role of Co-grinding in Enhancing the in Vitro Dissolution Characteristics of Itraconazole

P.V. Swamy, A.Sangram1, S.B. Shirsand, A.B. Prashant

Abstract: In the present study an attempt has been made to increase the dissolution rate of poorly water soluble drug itraconazole, by employing novel cogrinding method using four carriers, namely, lactose, cornstarch, pregelatinized starch and sodium starch glycolate. The coground mixtures were prepared in three different drug-carrier (w/w) ratios of 1:1, 1:3 and 1:5. The mixtures were evaluated for drug content uniformity, drug-carrier interaction ( FTIR) and dissolution characteristics. The formulation with drug-carrier ratio of 1:5 (itraconazole-pregelatinized starch) showed promising results with t70% value of 8 min compared to pure drug (t70%>90min). Capsules prepared from this mixture displayed six-fold increase in the dissolution efficiency compared to commercial capsule formulation of itraconazole (DE30min values of 66.86% and 10.60% respectively). Short term stability studies (at 40oC / 75% RH for 3 weeks) of the designed capsule formulation showed no significant changes in the drug content and t70% value (p<0.05). This study proves that cogrinding technique can be used for enhancing the in vitro dissolution characteristics of the poorly soluble drug itraconazole.

Introduction: The poor dissolution characteristics of relatively insoluble drugs have been a problem to the pharmaceutical industry. When an insoluble or sparingly soluble drug is administered orally, the rate and extent of absorption are controlled by the dissolution rate in the gastrointestinal fluids.
Itraconazole (ITR) is a triazole antifungal and has a broad spectrum of activity. It is used to treat fungal infections in immunocompromised and non-immunocompromised patients who have cryptococcosis, blastomycosis, and aspergillosis. It is practically insoluble in water and its absorption is dissolution rate limited.1 Therefore, in the present study an attempt has been made to increase its dissolution rate by novel co-grinding method. Though the solid dispersion technique is an attractive method in the dissolution enhancement of poorly water-soluble drugs, many challenges have limited its application in the design of the dosage forms.2 Some of the limitations are difficulty in pulverization and sifting of the dispersions, which are usually soft and tacky,3,4 poor flow and mixing properties, poor compressibility, drug-carrier incompatibility and poor stability5 of the dosage forms. Ordered mixing,6 roll mixing,7 complexation,8 cogrinding,9 cogrinding in presence of small amount of water10 are some of the alternative reported methods for enhancing the dissolution rate of poorly water-soluble drugs with an aim to the development of suitable formulation for oral use. Enhanced dissolution rate of ITR by the formulation of inclusion complexes with α, β, γ and hydroxypropyl β-cyclodextrins was reported11. In the present work, studies were carried out on the role of cogrinding in enhancing the in vitro dissolution characteristics of itraconazole using various excipients, namely, lactose (L), corn starch (CS), pregelatinized starch (PGS) and sodium starch glycolate (SSG) with a view to improve the dissolution rate and develop fast release formulations fulfilling the official dissolution requirements, thus enhancing the bioavailability of the drug.


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