Towards Integrated Drug Substance and Drug Product Design for an Active Pharmaceutical Ingredient Using Particle Engineering

Abstract

Abstract. A novel experimental approach describing the integration of drug substance and drug production design using particle engineering techniques such as sonocrystallization, high shear wet milling (HSWM) and dry impact (hammer) milling were used to manufacture samples of an active pharmaceutical ingredient (API) with diverse particle size and size distributions. The API instability was addressed using particle engineering and through judicious selection of excipients to reduce degradation reactions. API produced using a conventional batch cooling crystallization process resulted in content uniformity issues. Hammer milling increased fine particle formation resulting in reduced content uniformity and increased degradation compared to sonocrystallized and HSWM API in the formulation. To ensure at least a 2-year shelf life based on predictions using an Accelerated Stability Assessment Program, this API should have a D [v, 0.1] of 55 μm and a D [v, 0.5] of 140 μm. The particle size of the chief excipient in the drug product formulation needed to be close to that of the API to avoid content uniformity and stability issues but large enough to reduce lactam formation. The novel methodology described here has potential for application to other APIs.

The role of ultrasound in pharmaceutical production: sonocrystallization

“…Evaporation-based and cold-based sonocrystallization. The two classical ways to reach saturationevaporation (when the thermostability of the system was appropriate) [61,[70][71][72] or cooling (when the decrease in solubility of the target drug was significant enough) [40][41][42]60,73] have been assisted by US, and the typical crystallization parameters have been improved in all instances. [42,72] Salting-out sonocrystallization.…”

“…The irreproducible performance of US cleaning baths and the decline of power with the working time are not taken into account by the authors who use them for crystallization purposes without considering the influence of these aspects on the results. US probes are the most used devices to favour drug crystallization, usually commercial probes that apply their characteristic effect on either, commercial or laboratory‐designed cells, working in a batch or flow regime . US laboratory reactors (also known as US processors), either commercial or especially designed, are usually more versatile, as they can provide different US frequencies in narrow or wide ranges, and variable US power that can reach more than 1000 W …”

“…US probes are the most used devices to favour drug crystallization, usually commercial probes that apply their characteristic effect on either, commercial [36][37][38] or laboratory-designed cells, [2,39] working in a batch [40] or flow regime. [40,41] US laboratory reactors (also known as US processors), either commercial or especially designed, are usually more versatile, as they can provide different US frequencies in narrow [42] or wide ranges, [40] and variable US power that can reach more than 1000 W. [19] US probes or tips are scaled down from the conventional laboratory size to work with lg-to-mg samples close to the discovery phase of pharmaceutical development where only very small amounts of material are available. [43] These devices are usually made on titanium, except when they work in the presence of microwaves that require probes or tips of glass.…”

“…Measurements of particle size and size distribution obtained. Reproduced from[41] with permission of the American Association of Pharmaceutical Scientists.…”

Integration of active pharmaceutical ingredient solid form selection and particle engineering into drug product design

“…The methods or models described in this section can be used retrospectively to assess risks once an API has been produced, but more importantly in the context of solid form selection they can be used to help guide the appropriate properties needed from the API solid form. Kougoulos et al [84] provided a detailed example of application of content uniformity and the dissolution models, together with modelling of accelerated stability data. Based on the impact of fine particles on chemical stability and coarser particles on content uniformity and dissolution, they derived a target particle size specification for D[v, 0.1] and D[v,0.5].…”