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1.
Eur J Pharm Sci ; 165: 105921, 2021 Oct 01.
Article in English | MEDLINE | ID: mdl-34229077

ABSTRACT

For oral solid dosage forms, disintegration and dissolution properties are closely related to the powders and particles used in their formulation. However, there remains a strong need to characterize the impact of particle structures on tablet compaction and performance. Three-dimensional non-invasive tomographic imaging plays an increasingly essential role in the characterization of drug substances, drug product intermediates, and drug products. It can reveal information hidden at the micro-scale which traditional characterization approaches fail to divulge due to a lack of resolution. In this study, two batches of spray-dried particles (SDP) and two corresponding tablets of an amorphous product, merestinib (LY2801653), were analyzed with 3D X-Ray Microscopy. Artificial intelligence-based image analytics were used to quantify physical properties, which were then correlated with dissolution behavior. The correlation derived from the image-based characterization was validated with conventional laboratory physical property measurements. Quantitative insights obtained from image-analysis including porosity, pore size distribution, surface area and pore connectivity helped to explain the differences in dissolution behavior between the two tablets, with root causes traceable to the microstructure differences in their corresponding SDPs.


Subject(s)
Artificial Intelligence , Microscopy, Electron, Scanning , Particle Size , Powders , Solubility , Tablets , X-Rays
2.
Annu Rev Chem Biomol Eng ; 9: 253-281, 2018 06 07.
Article in English | MEDLINE | ID: mdl-29879381

ABSTRACT

The pharmaceutical industry has found new applications for the use of continuous processing for the manufacture of new therapies currently in development. The transformation has been encouraged by regulatory bodies as well as driven by cost reduction, decreased development cycles, access to new chemistries not practical in batch, improved safety, flexible manufacturing platforms, and improved product quality assurance. The transformation from batch to continuous manufacturing processing is the focus of this review. The review is limited to small, chemically synthesized organic molecules and encompasses the manufacture of both active pharmaceutical ingredients (APIs) and the subsequent drug product. Continuous drug product is currently used in approved processes. A few examples of production of APIs under current good manufacturing practice conditions using continuous processing steps have been published in the past five years, but they are lagging behind continuous drug product with respect to regulatory filings.


Subject(s)
Pharmaceutical Preparations/chemistry , Technology, Pharmaceutical , Dosage Forms/standards , Drug Industry , Pharmaceutical Preparations/chemical synthesis , Pharmaceutical Preparations/standards , Quality Control , Technology, Pharmaceutical/standards
3.
Science ; 356(6343): 1144-1150, 2017 Jun 16.
Article in English | MEDLINE | ID: mdl-28619938

ABSTRACT

Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.


Subject(s)
Antineoplastic Agents/chemical synthesis , Chemistry, Pharmaceutical/methods , Drug Industry/methods , Pharmaceutical Preparations/chemical synthesis , Chemistry, Pharmaceutical/standards , Drug Industry/standards , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/standards
4.
J Pharm Sci ; 99(1): 51-75, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19521966

ABSTRACT

A strategy for physical property control of a drug substance has been developed that utilizes a science-based approach to define key drivers for particle control. These drivers are based on in vivo performance (or expected performance), content uniformity of the drug substance in drug product, and manufacturability of drug product. Quality by design principles have been used in developing the strategy. The strategy has been designed to provide expectations in terms of particle control at each state of development, translating to early-phase projects and carrying through until launch and beyond.


Subject(s)
Chemical Phenomena , Drug Design , Small Molecule Libraries/chemistry , Small Molecule Libraries/chemical synthesis , Technology, Pharmaceutical/methods , Administration, Oral , Decision Trees , Microscopy, Electron, Scanning , Models, Biological , Models, Chemical , Particle Size , Pharmacokinetics , Software , Surface Properties , Technology, Pharmaceutical/instrumentation
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