Pulmonary inhalation is increasingly being selected as a preferred route for the delivery of both small and large drug macromolecules for the treatment of a range of pathologies. The direct crystallization of micronized powders, in particular, paracetamol, remains difficult, as it requires the ability to work in high solution supersaturations where agglomeration, wall crusting, and heterogeneous nucleation hinder the control of crystal size and crystal size distribution. Polymer additives are recognized to help drive the production of a given polymorph or controlling crystal shape by means of adsorption on the crystal surface. With the aim of exploiting the polymer-control nucleation and growth of crystals for enhanced direct crystallization of micronized powders, batch cooling crystallization of paracetamol in water was carried out in the presence of 0.1−0.8% w/w hydroxypropyl methylcellulose (HPMC). In the presence of polymer, the onset of nucleation was delayed and extended beyond the cooling time of the solution, resulting in an isothermal cooling crystallization and the production of micronized paracetamol with a mean crystal size D 50 , in the range of 15−20 μm and an improved crystal size distribution. Equally, the rate generation of solution cloudiness was reduced by over 3-fold for the highest HPMC concentration tested, with no detectable impact on final product yield. The mechanisms for nucleation delay and growth inhibition by HPMC is unknown; however, a modification of crystal's shape observed upon the addition of HPMC to the solution suggested it might be related to mass transfer limitations and intermolecular hydrogen bonding between the large HPMC and the small drug molecules. This technique can potentially be used for direct crystallization of other micronized drugs.

We previously found that dried live bacteria of a vaccine strain can be temporarily sensitive to bile acids and suggested that Bile Adsorbing Resins (BAR) can be used in oral vaccine tablets to protect dried bacteria from intestinal bile. Here, we report a quantitative analysis of the ability of BAR to exclude the dye bromophenol blue from penetrating into matrix tablets and also sections of hard capsule shells. Based on this quantitative analysis, we made a fully optimised formulation, comprising 25% w/w of cholestyramine in Vcaps™ HPMC capsules. This gave effectively 100% protection of viability from 4% bile, with 4200-fold more live bacteria recovered from this formulation compared to unprotected dry bacteria. From the image analysis, we found that the filler material or compaction force used had no measurable effect on dye exclusion but did affect the rate of tablet hydration. Increasing the mass fraction of BAR gave more exclusion of dye up to 25% w/w, after which a plateau was reached and no further dye exclusion was seen. More effective dye exclusion was seen with smaller particle sizes (i.e. cholestyramine) and when the BAR was thoroughly dried and disaggregated. Similar results were found when imaging dye penetration into capsule sections or tablets. The predictions of the dye penetration study were tested using capsules filled with dried attenuated Salmonella vaccine plus different BAR types, and the expected protection from bile was found, validating the imaging study. Surprisingly, depending on the capsule shell material, some protection was given by the capsule alone without adding BAR, with Vcaps™ HPMC capsules providing up to 174-fold protection against 1% bile; faster releasing Vcaps Plus™ HPMC capsules and Coni Snap™ gelatin capsules gave less protection.