Investigation of possible solubility and dissolution advantages of cocrystals, I: Aqueous solubility and dissolution rates of ketoconazole and its cocrystals as functions of pH.

Jaydip M Vasoya,Abu T.M Serajuddin,Ankita V Shah

doi:10.5599/admet.661

Jaydip M Vasoya, Abu T.M Serajuddin + Show 1 more

Open Access

https://doi.org/10.5599/admet.661

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Journal: ADMET & DMPK	Publication Date: Apr 3, 2019
Citations: 16	License type: cc-by

Affiliation: St. John's University, Vector (United States)

Abstract

Since there are conflicting reports in the literature on solubility and dissolution advantages of cocrystals over free forms, we systematically studied solubility and intrinsic dissolution rates of a weakly basic drug, ketoconazole, and its cocrystals with fumaric acid and succinic acid as functions of pH to determine what advantages cocrystals provide. pH-solubility profiles were determined in two different ways: one by lowering pH of ketoconazole aqueous suspensions using HCl, fumaric acid and succinic acid, and the other by adjusting pH of cocrystal suspensions using respective coformer acids or NaOH. Similar pH-solubility profiles were obtained whether free base or cocrystals were used as starting materials to determine solubility. With the addition of fumaric and succinic acids to aqueous suspensions of free base to lower pH, the maximum solubility (pHmax) was reached at pH ~3.5-4.0, below which the solubility decreased and cocrystals formed. The solubility, however, continued increasing when HCl was added to ketoconazole suspension as no cocrystal or salt was formed. During determination of cocrystal solubility, a conversion to free base was observed when pH was raised above pHmax. Thus, pH-solubility profiles of cocrystals resembled solubility profiles commonly encountered with salts. Above pHmax, both free base and cocrystal had similar solubility under identical pH conditions; the solubility of cocrystal was higher only if the pH differed. In contrast, intrinsic dissolution rates of cocrystals at pH>pHmax under identical bulk pH were much higher than that of free ketoconazole since cocrystals had lower microenvironmental pH at the dissolving surface, where the solubility was high. Thus, cocrystals of basic drugs can potentially provide higher dissolution rates under intestinal pH conditions.

Highlights

Crystalline forms of acidic and basic drugs or their salts have traditionally been used as active pharmaceutical ingredients (API) [1]
Ketoconazole-fumaric acid and ketoconazole-succinic acid cocrystals prepared by the solvent evaporation method in the present investigation were analyzed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) to assess their crystallinity and purity
The relatively sharp endotherms indicated that the cocrystals were highly crystalline, and the absence of any separate peaks for ketoconazole alone or free acids in DSC scans confirmed the absence of any impurity due to the presence of unconverted ketoconazole or coformers in cocrystals

Summary

Introduction

Crystalline forms of acidic and basic drugs or their salts have traditionally been used as active pharmaceutical ingredients (API) [1]. It is evident that until the onset of cocrystal formation (i.e, above the pHmax), pH-solubility profiles were similar whether they were determined by adjusting pH with fumaric acid, succinic acid or HCl. The solubility is similar to that shown in Fig. 5 by increasing pH of cocrystal solutions with NaOH.

Results

Conclusion