Developing a Batch Isolation Procedure and Running It in an Automated Semicontinuous Unit: AWL CFD25 Case Study.

A key challenge during the transition from laboratory/small batch to continuous manufacturing is the development of a process strategy that can easily be adopted for a larger batch/continuous process. Industrial practice is to develop the isolation strategy for a new drug/process in batch using the design of experiment (DoE) approach to determine the best isolation conditions and then transfer the isolation parameters selected to a large batch equipment/continuous isolation process. This stage requires a series of extra investigations to evaluate the effect of different equipment geometry or even the adaptation of the parameters selected to a different isolation mechanism (e.g., from dead end to cross flow filtration) with a consequent increase of R&D cost and time along with an increase in material consumption. The CFD25 is an isolation device used in the first instance to develop an isolation strategy in batch (optimization mode) using a screening DoE approach and to then verify the transferability of the strategy to a semicontinuous process (production mode). A d-optimal screening DoE was used to determine the effect of varying the input slurry. Properties such as solid loading, particle size distribution, and crystallization solvent were investigated to determine their impact on the filtration and washing performance and the characteristics of the dry isolated product. A series of crystallization (ethanol, isopropanol, and 3-methylbutan-1-ol) and wash solvents (n-heptane, isopropyl acetate and n-dodcane) were used for the process. To mimic a real isolation process, paracetamol-related impurities, acetanilide and metacetamol, were dissolved in the mother liquor. The selected batch isolation strategy was used for the semicontinuous isolation run. Throughput and filtration parameters, such as cake resistance and flow rate, cake residual liquid content and composition, cake purity, particle-particle aggregation, and extent and strength of agglomerates, were measured to evaluate the consistency of the isolated product produced during a continuous experiment and compared with the isolated product properties obtained during the batch process development. Overall, the CFD25 is a versatile tool which allows both new chemical entity process development in batch and the production of the active pharmaceutical ingredient in semicontinuous mode using the same process parameters without changing equipment. The isolated product properties gained during the semicontinuous run are overall comparable between samples. The residual solvent content and composition differs between some samples due to filter plate blockage. In general, the mean properties obtained during semicontinuous running are comparable with the product properties simulated using the DoE.

Effect of encapsulating a pseudo-decapeptide containing arginine on PLGA: a solid-state NMR study.

The effects of incorporating an amorphous decapeptide in PLGA on the cooperative and local motions of the polymer chains have been evaluated. Whereas assessment of the bulk properties is used traditionally for studies of host-guest interactions, there are only rare examples where molecular-level understanding of such amorphous host-guest systems has been sought. Moreover, addressing the mechanism of interactions and stabilisation of a drug in a polymeric network is a key factor for the achievement of reproducibility of the formulations and ultimately the preparation of composites able to deliver drugs with consistency. We present a methodology combining the study of the dynamics by solid-state NMR and the characterisation of the bulk properties to address and localise the presence of interactions in PLGA/guest composites. The results (estimation of relaxation times, 2D wideline separation and T(g) measurements) suggested (1) the existence of a drug-polymer solid solution and (2) significant changes in the local dynamics of both the drug and the polymer in their composites depending on the loading level. The changes in the local dynamics as well as in the cooperative motions of the polymer chains in the composites were attributed to the formation of guest-polymer interactions. Differentiation of the affinity of glycolide or lactide units for interactions was also apparent.

Effect of encapsulating arginine containing molecules on PLGA: a solid-state NMR study.

Design of polymer-drug composites based on the lactide/glycolic acid often rely on the chemical complementarity between the polymer and functional groups in a pharmaceutical guest. We previously characterised decapeptide (AZD)/poly(D,L-lactide-co-glycolide) (PLGA) film formulations aiming at localising the interacting groups responsible for the changes in the bulk properties of the polymer matrix and understanding the mechanism of stabilisation of the drug into the polymer matrix. The results suggested interactions to occur between the arginine residue in the peptide and the carbonyl end group of the polymer chains. In order to clarify the role of arginine in directing the drug-polymer interactions, arginine and hexapeptide containing arginine were encapsulated in a PLGA 50/50 polymer. Variable temperature T1 rh H measurements and WISE experiments indicated significant changes in the local dynamics of the polymer chains. These effects were enhanced near and above T(g) suggesting the presence of guests promote the appearance of backbone motion of the polymer chains. The localisation of the interactions on the carbonyl groups of the polymer was further confirmed by the WISE experiments.