Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

Continuous manufacturing is widely used for the production of commodity products. Currently, it is attracting increasing interest from the pharmaceutical industry and regulatory agencies as a means to provide a consistent supply of medicines. Crystallisation is a key operation in the isolation of the majority of pharmaceuticals and has been demonstrated in a continuous manner on a number of compounds using a range of processing technologies and scales. Whilst basic design principles for crystallisations and continuous processes are known, applying these in the context of rapid pharmaceutical process development with the associated constraints of speed to market and limited material availability is challenging. A systematic approach for continuous crystallisation process design is required to avoid the risk that decisions made on one aspect of the process conspire to make a later development step or steps, either for crystallisation or another unit operation, more difficult. In response to this industry challenge, an innovative system-wide approach to decision making has been developed to support rapid, systematic, and efficient continuous seeded cooling crystallisation process design. For continuous crystallisation, the goal is to develop and operate a robust, consistent process with tight control of particle attributes. Here, an innovative system-based workflow is presented that addresses this challenge. The aim, methodology, key decisions and output at each at stage are defined and a case study is presented demonstrating the successful application of the workflow for the rapid design of processes to produce kilo quantities of product with distinct, specified attributes suited to the pharmaceutical development environment. This work concludes with a vision for future applications of workflows in continuous manufacturing development to achieve rapid performance based design of pharmaceuticals

Pharmaceutical polymorphs quantified with transmission Raman spectroscopy

The quantification of polymorphs in dosage forms is important in the pharmaceutical industry. Conventional Raman spectroscopy of solid-state pharmaceuticals may be used for this, but it has some limitations such as sub-sampling and fluorescence. These problems can be mitigated through the use of transmission Raman spectroscopy (TRS). The efficacy of TRS measurements for the prediction of polymorph content was evaluated using a ranitidine hydrochloride test system. Four groups of ranitidine hydrochloride-based samples were prepared: three containing form I and II ranitidine hydrochloride and microcrystalline cellulose (spanning the ranges 0-10%, 90-100% and 0-100% form I fraction of total ranitidine hydrochloride), and a fourth group comprising form I ranitidine hydrochloride (0-10%) spiked commercial formulation. Transmission and conventional Raman spectroscopic measurements were recorded from both capsules and tablets of the four sample groups. Prediction models for polymorph and total ranitidine hydrochloride content were more accurate for the tablet than for the capsule systems. TRS was found to be superior to conventional backscattering Raman spectroscopy in the prediction of polymorph and total ranitidine hydrochloride content. The prediction model calculated for form I content across the 0-100% range was appropriate for process control [ratio of prediction to deviation (RPD) equal to 14.62 and 7.42 for tablets and capsules, respectively]. The 10% range calibrations for both form I and total ranitidine hydrochloride content were sufficient for screening (RPDs greater than 2.6). TRS is an effective tool for polymorph process control within the pharmaceutical industry. © 2011 John Wiley & Sons, Ltd.Article in Pres

Cocrystal formation of niclosamide and urea in supercritical CO2 and impact of cosolvent

A cocrystal of niclosamide and urea was attempted for the first time using a crystallization in supercritical solvent (CSS). Experiments were conducted at 40 °C or 60 °C between 3.3 and 29.4 MPa in CO2. Cocrystal formation showed a dependence on the state of CO2 with no cocrystal formation below the critical point and consistently showed partial conversion above the critical point. The addition of 0.5 mL (2.7–3.5 mol%) cosolvent was found to have significant impact on cocrystal formation at 40 °C and 20 MPa. Addition of 2-propanol increased cocrystal formation by between 50 % and 60 % compared to neat scCO2, while cyclohexane reduced cocrystal formation by between 20 % and 35 %, and water completely hindered cocrystal formation. The impact of hold time, cosolvent, solubility in relation to ternary phase diagrams, and inter- and intra-molecular hydrogen bonding are discussed