Correlations between surface composition and aerosolization of jet-milled dry powder inhaler formulations with pharmaceutical lubricants.

Co-jet-milling drugs and lubricants may enable simultaneous particle size reduction and surface coating to achieve satisfactory aerosolization performance. This study aims to establish the relationship between surface lubricant coverage and aerosolization behavior of a model drug (ciprofloxacin HCl) co-jet-milled with lubricants [magnesium stearate (MgSt) or l-leucine]. The co-jet-milled formulations were characterized for particle size, morphology, cohesion, Carr's index, and aerosolization performance. The surface lubricant coating was assessed by probing surface chemical composition using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary-ion mass spectrometry (ToF-SIMS). The effects of co-jet-milling on the surface energy and in vitro dissolution of ciprofloxacin were also evaluated. Our results indicated that, in general, the ciprofloxacin co-jet-milled with l-leucine at >0.5% w/w showed a significant higher fine particle fraction (FPF) compared with the ciprofloxacin jet-milled alone. The FPF values plateau at or above 5% w/w for both MgSt and l-leucine. We have established the quantitative correlations between surface lubricant coverage and aerosolization in the tested range for each of the lubricants. More importantly, our results suggest different mechanisms to improve aerosolization for MgSt-coating and l-leucine-coating, respectively: MgSt-coating reduces inter-particulate interactions through the formation of low surface energy coating films, while l-leucine-coating not only reduces the surface energy but also creates rough particle surfaces that reduce inter-particulate contact area. Furthermore, surface coatings with 5% w/w MgSt (which is hydrophobic) did not lead to substantial changes in in vitro dissolution. Our findings have shown that the coating structure/quality and their effects could be highly dependent on the process and the coating material. The findings from this mechanistic study provide fundamental understanding of the critical effects of MgSt and l-leucine surface coverages on aerosolization and powder flow properties of inhalation particles.

Cyclodextrin Reduces Intravenous Toxicity of a Model Compound.

Solubilization of new chemical entities for toxicity assessment must use excipients that do not negatively impact drug pharmacokinetics and toxicology. In this study, we investigated the tolerability of a model freebase compound, GDC-0152, solubilized by pH adjustment with succinic acid and complexation with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) to enable intravenous use. Solubility, critical micelle concentration, and association constant with HP-ß-CD were determined. Blood compatibility and potential for hemolysis were assessed in vitro. Local tolerability was assessed after intravenous and subcutaneous injections in rats. A pharmacokinetic study was conducted in rats after intravenous bolus administration. GDC-0152 exhibited pH-dependent solubility that was influenced by self-association. The presence of succinic acid increased solubility in a concentration-dependent manner. HP-ß-CD alone also increased solubility, but the extent of solubility enhancement was significantly lower than succinic acid alone. Inclusion of HP-ß-CD in the solution of GDC-0152 improved blood compatibility, reduced hemolytic potential by ∼20-fold in vitro, and increased the maximum tolerated dose to 80 mg/kg.

Quantitative X-Ray Microcomputed Tomography Assessment of Internal Tablet Defects.

Physical tablet defects are related to internal structural defects that are not easily assessed by the traditional methods, such as dusting, laminating, or fracturing during appearance, friability, or hardness testing. Also, these methods do not allow objective and quantitative investigation of the role of formulation and process variables, which is essential for quality-by-design drug product development. In this study, an X-ray microcomputed tomography (XµCT) method to analyze internal tablet defects is developed using tablets from a quality-by-design design-of-experiment study. The design of experiment investigated the effect of roller compaction roll force, filler composition, and the amount of magnesium stearate on tablet quality attributes. Average contiguous void volume by optical image processing and fracture size distribution and direction by artificial intelligence-based image processing quantified the internal tablet fracture severity. XµCT increased formulation and process knowledge in support of scale-up manufacturing. We demonstrated how XµCT can be incorporated as a part of a holistic approach to quantitatively identify and mechanistically assess the risks of internal tablet defects. Furthermore, expanding the use of XµCT with an artificial intelligence-based quantitative analysis can deepen our tableting knowledge from an empirical understanding to a mechanistic understanding of compaction phenomenon.

Integrated Application of Quality-by-Design Principles to Drug Product Development: A Case Study of Brivanib Alaninate Film-Coated Tablets.

Modern drug product development is expected to follow quality-by-design (QbD) paradigm. At the same time, although there are several issue-specific examples in the literature that demonstrate the application of QbD principles, a holistic demonstration of the application of QbD principles to drug product development and control strategy, is lacking. This article provides an integrated case study on the systematic application of QbD to product development and demonstrates the implementation of QbD concepts in the different aspects of product and process design for brivanib alaninate film-coated tablets. Using a risk-based approach, the strategy for development entailed identification of product critical quality attributes (CQAs), assessment of risks to the CQAs, and performing experiments to understand and mitigate identified risks. Quality risk assessments and design of experiments were performed to understand the quality of the input raw materials required for a robust formulation and the impact of manufacturing process parameters on CQAs. In addition to the material property and process parameter controls, the proposed control strategy includes use of process analytical technology and conventional analytical tests to control in-process material attributes and ensure quality of the final product.