Crystal Structure and Twisted Aggregates of Oxcarbazepine Form III.

Polymorphism and crystal habit play vital roles in dictating the properties of crystalline materials. Here, the structure and properties of oxcarbazepine (OXCBZ) form III are reported along with the occurrence of twisted crystalline aggregates of this metastable polymorph. OXCBZ III can be produced by crystallization from the vapor phase and by recrystallization from solution. The crystallization process used to obtain OXCBZ III is found to affect the pitch, with the most prominent effect observed from the sublimation-grown OXCBZ III material where the pitch increases as the length of aggregates increases. Sublimation-grown OXCBZ III follows an unconventional mechanism of formation with condensed droplet formation and coalescence preceding nucleation and growth of aggregates. A crystal structure determination of OXCBZ III from powder X-ray diffraction methods, assisted by crystal structure prediction (CSP), reveals that OXCBZ III, similar to carbamazepine form II, contains void channels in its structure with the channels, aligned along the c crystallographic axis, oriented parallel to the twist axis of the aggregates. The likely role of structural misalignment at the lattice or nanoscale is explored by considering the role of molecular and closely related structural impurities informed by crystal structure prediction.

Manufacture of tablets with structurally-controlled drug release using rapid tooling injection moulding.

With advancements in the pharmaceutical industry pushing more towards tailored medicines, novel approaches to tablet manufacture are in high demand. One of the main drivers towards micro-scale batch production is the ability to fine-tune drug release. This study demonstrates the use of rapid tooling injection moulding (RTIM) for tablet manufacture. Tablets were manufactured with varying structural features to alter the surface area whilst maintaining the same volume, resulting in differing specific surface area (SSA). The precision of this technique is evaluated based on eleven polymer formulations, with the tablets displaying <2% variability in mass. Further tablets were produced containing paracetamol in three different polymer-based formulations to investigate the impact of SSA on the drug release. Significant differences were observed between the formulations based on the polymers polyvinyl alcohol (PVA) and Klucel ELF. The polymer base of the formulation was found to be critical to the sensitivity of the drug release profile to SSA modification. The drug release profile within each formulation was modified by the addition of structural features to increase the SSA.

Mefenamic acid solid dispersions: Impact of formulation composition on processing parameters, product properties and performance.

The objective of this study was to develop an immediate release (IR), crystalline solid dispersion (CSD) formulation of Mefenamic acid (MFA) by hot-melt-extrusion (HME) and assess the impact of drug loading on process parameters, product physico-chemical properties and product performance. An HME process to produce a range of MFA-Soluplus®-Sorbitol polymer matrix CSD formulations was developed based on rheological screening assays of physical mixtures (PM). The impact of drug loading on process parameters was compared to the impact of drug loading on the physico-chemical properties of formulations. Based on process and product data, three groupings of API drug loading were identified: sub-saturated, saturated, and supersaturated systems. CSD formulations were obtained for 20-50% (w/w) drug loading containing the stable polymorphic form I of MFA. CSD formulations predominantly improved the consistency of the product performance. An Amorphous Solid Dispersion (ASD) was obtained for 10% (w/w) drug loading, exhibiting faster drug release even at physiologically relevant pH. This study illustrates the impact of drug loading on process and product characteristics and how a better understanding of maximum API solubility in a given polymer system can improve targeted formulation development.

Improving Consistency for a Mefenamic Acid Immediate Release Formulation.

The objective of this study was to develop an immediate release dose form containing 250 mg Mefenamic acid (MFA) presented as a crystalline solid dispersion in order to achieve improved consistency in drug release through a simplified formulation compared to a commercial product. An MFA-Soluplus®-Sorbitol polymer matrix was developed using an HME process based on rheological screening assays of physical mixtures. The physico-chemical properties of these formulations were assessed by thermal analysis, FTIR, mechanical testing and SEM image analysis, confirming the crystalline character and stable polymorphic form I of the API in the polymer matrix. A faster release and a significant improvement in consistency (±6%) of drug release was observed compared to a commercially available MFA product (±17%) (250 mg capsule). This study illustrates advantages of applying a structured development program aimed at retaining API physical properties in the final dosage form.