Category: Formulation and Quality
Purpose: The number of Active Parametrical Ingredients (API) with less than ideal physiochemical properties, such as poor solubility and physical / chemical stability has increased over the last decade. The solid form of an API strongly influences these properties and it is vitally important to understand and manufacture the appropriate solid form. Salts and co-crystals have been identified as viable solid forms that may improve the pharmaceutical properties of development candidates.
However, crystallisation of multi-component forms using traditional solvent-based methods can be troublesome, especially on scale, as knowledge of the ternary phase diagram between the constituents and the solvent is necessary to generate the desired form in good yield. Further to this, multi-component generation using environmentally friendly methods such as liquid-assisted grinding and sonication often cannot be used to scale up large quantities of material. The aim of this study was to identify a suitable, green mechanochemical technique to selectively generate multi-component forms on scale.
Methods: Hot melt extrusion (HME) is an area of growing interest, with more than 100 pharmaceutical applications published in the last decade. HME is a green technology which offers a number of advantages over traditional pharmaceutical processes, including absence of solvents and reduction of processing steps. Additionally, HME benefits include continuous operation, easy tech-transfer and particle engineering (solid dispersions for improved solubility and bioavailability). Hot Melt Extrusion and traditional solution-based crystallisation methods were assessed to determine impact of specific parameters for selectively generating salt and co-crystal forms of pyrimethanil, a broad spectrum fungicide.
Results: Pyrimethanil, is able to form both a salt and co-crystal form with 3-nitrobenzoic acid. Previous studies have shown the co-crystal to be the thermodynamic product and is readily generated via solution crystallisation. However, the salt is a metastable kinetic form, isolation of which has been shown to be challenging. The salt form appears as a white powder whilst the co-crystal forms appears as a distinctive yellow powder. The results of this study were that we were able to selectively crystallise the desired form (salt or co-crystal) of pyrimethanil/3-nitrobenzoic acid for large scale synthesis using HME.
Conclusion: In this study, we demonstrate how through careful tuning of procedure parameters, such as temperature and mixing speed, the salt or co-crystal form can be selectively isolated in pure phase using HME.
Mark Wright– Scientist, Johnson Matthey, Cambridge, England, United Kingdom
Dominic Holloway– Cambridge, England, United Kingdom
Thierry Bonnaud– Lead Scientist, Johnson Matthey, Cambridge, England, United Kingdom
Osama Suleiman– Team Leader, Johnson Matthey, Cambridge, England, United Kingdom