Solid-state properties of pharmaceuticals

Abstract

The complexity of polymorphic interconversions emphasized the need for a well defined study to investigate the solid-state properties of selected pharmaceutical solids, the thermodynamic stability of various polymorphic forms and to explore the effect of heat and moisture on the stability of these polymorphic forms. It was decided to embark on such studies focusing on the following active pharmaceutical ingredients: venlafaxine HCI (freely water soluble), fluconazole (slightly water soluble) and mebendazole (practically insoluble in water). Three of the seven commercially available mebendazole products (tablets) contained polymorph C and traces of polymorph A, the other four products contained mebendazole polymorph C. Moisture, increased temperatures and the presence of polymorph A traces in products played an integral role in the thermodynamic stability of mebendazole polymorph C fraction in the tablets. The three mentioned factors influenced the dissolution behaviour negatively. The rate of the polymorph C -> polymorph A conversion was investigated and found to be higher for tablets stored at 40°C & 75% RH, compared to those stored at 30°C & 65% RH. Products which contained traces of polymorph A revealed a higher rate of polymorph transformation (polymorph C -> polymorph A) compared to those who initially contained only polymorph C. Kinetic analysis of the transformations abided JMAEK fits for the isothermal conversion of mebendazole polymorph C -» A in the tablets. From the Avrami exponent (n) it could be suggested that the rate-limiting step for the formation of polymorph A in these products was diffusion. The importance of these transformations were Illustrated by the changes in the half-life (ti/2 = 0.693//c) and shelf-life (t90 = 0.105//r) of the polymorph C fractions in the products. It was also observed that the metastable polymorphic forms of mebendazole (i.e. polymorphs B &. C) undergo an aqueous mediated phase transition (at increased temperatures) to convert to the thermodynamic stable, polymorph A. A new crystal form of venlafaxine HCI (Form 5) was successfully prepared and characterised. Form 5 was classified as a metastable polymorph of venlafaxine HCI which is enantiotropically related to Form 1, and converts to Form 1 when heated at 150°C or converts to Form 2 when heated at 175 °C for two hours. Solution microcalorimetry revealed that the dissolution of Form 1 and Form 5 in water was an exothermic reaction and that an increase in temperature inhibits the dissolution reaction of the mentioned crystal forms, decreasing the solubility thereof. Exposure of venlafaxine HCI Form 1 to moisture did not induce any polymorphic transition. However, the metastable form, Form 5 absorbed moisture and transformed into a monohydrate when exposed to 85% RH at 30°C. The hydration of Form 5 when exposed to 85% RH & 30°C (anhydrous form -> monohydrated form) was accompanied by a morphological change to accommodate the absorbed water molecules in the hydrated Form 5. Form 5 did not undergo any polymorphic transition when exposed to 65 & 75% RH at 30°C but revealed unpredictable thermal behaviour. VT-XRPD studies revealed that when the hydrated Form 5 was dehydrated it converted to the anhydrous Form y. The monohydrated crystal from (Form MH) and the anhydrous form (Form I) of fiuconazole were successfully prepared and VT-XRPD studies confirmed that dehydration of Form MH resulted in the formation of the thermodynamic stable Form I. Form MH and Form I remained stable when exposed to 0-85% RH & 30°C and 0-75% RH & 30°C respectively. Upon exposure to 85% RH & 30°C for 7 days, Form I incorporated water molecules into the crystal lattice and transformed into a hydrated Form I. The dehydration mechanism and kinetic parameters for the hydrated Form I and Form MH were compared. It was revealed that the activation energy for dehydration of the hydrated Form I was slightly higher compared to that for Form MH due to the fact that dehydration and an endothermic rearrangement occurred simultaneously, contributing to the slightly higher dehydration activation energy observed for the hydrated Form I, also explaining the absence of the rearrangement endotherm in the DSC thermogram of the hydrated Form I at 101 "C. The DSC thermogram for the dehydration of Form MH revealed two separate endothermic events (a dehydration and a rearrangement endotherm) showing that dehydration of Form MH occurred in two steps and dehydration of the hydrated Form I in one step. A monohydrated crystal structure proves to be the highest and most stable hydration level for fiuconazole.