Current Approaches to Design Space Development and Regulatory Applications for Drug Products: Findings from the IQ Utilization of Design Space for Filings Working Group Survey.

PURPOSE: The concept of a Design Space (DSp) was introduced in ICH Q8 as a tool within the quality-by-design (QbD) approach to pharmaceutical development with the intent of being globally applicable. However, there appears to be variance in the regulatory agency expectations in pharmaceutical product filing and implementation of DSp. This paper presents some of the current industry perspective on design space. METHODS: The Utilization of Design Space for Filings (UDSpF) Working Group in the Innovation and Quality (IQ) Consortium conducted a survey to establish a baseline for the current understanding of DSp among IQ member companies and assess the similarities and/or differences in strategies when filing a DSp. The survey focused on how IQ member companies approach DSp development, the primary drivers for the DSp, the presentation of the DSp in the filing, DSp verification and the benefits and flexibility anticipated and/or realized. RESULTS: A total of 14 responses were received and analyzed representing a small sample size but a large proportion of the innovator industry/large pharmaceutical companies. The survey results revealed that DSp is not yet a commonplace for small molecule drug products and may not even be utilized as much in large molecule drug products. The benefits of DSp, with respect to enhanced process understanding, are well understood by the sponsors; however, the benefits of filed DSp with respect to manufacturing flexibility are not fully realized in the commercial lifecycle of the product. There are also challenges in gaining consistent buy-in/value proposition for DSp among cross-functional teams within organizations. CONCLUSIONS: There are still gaps in design space implementation for its full benefit in the pharmaceutical industry. The WG has presented a unified view from member companies on the approach to DSp considering when/where the DSp experiments are conducted and on the extent of the DSp development proposed in a dossier.

Characterization of Phase Separation Propensity for Amorphous Spray Dried Dispersions.

A generalized screening approach, applying isothermal calorimetry at 37 °C 100% RH, to formulations of spray dried dispersions (SDDs) for two active pharmaceutical ingredients (APIs) (BMS-903452 and BMS-986034) is demonstrated. APIs 452 and 034, with similar chemotypes, were synthesized and promoted during development for oral dosing. Both APIs were formulated as SDDs for animal exposure studies using the polymer hydroxypropylmethlycellulose acetyl succinate M grade (HPMCAS-M). 452 formulated at 30% (wt/wt %) was an extremely robust SDD that was able to withstand 40 °C 75% RH open storage conditions for 6 months with no physical evidence of crystallization or loss of dissolution performance. Though 034 was a chemical analogue with similar physical chemical properties to 452, a physically stable SDD of 034 could not be formulated in HPMCAS-M at any of the drug loads attempted. This study was used to develop experience with specific physical characterization laboratory techniques to evaluate the physical stability of SDDs and to characterize the propensity of SDDs to phase separate and possibly crystallize. The screening strategy adopted was to stress the formulated SDDs with a temperature humidity screen, within the calorimeter, and to apply orthogonal analytical techniques to gain a more informed understanding of why these SDDs formulated with HPMCAS-M demonstrated such different physical stability. Isothermal calorimetry (thermal activity monitor, TAM) was employed as a primary stress screen wherein the SDD formulations were monitored for 3 days at 37 °C 100% RH for signs of phase separation and possible crystallization of API. Powder X-ray diffraction (pXRD), modulated differential scanning calorimetry (mDSC), Fourier transform infrared spectroscopy (FTIR), and solid state nuclear magnetic resonance (ssNMR) were all used to examine formulated SDDs and neat amorphous drug. 452 SDDs formulated at 30% (wt/wt %) or less did not show phase separation behavior upon exposure to 37 °C 100% RH for 3 days. 034 SDD formulations from 10 through 50% (wt/wt %) all demonstrated thermal traces consistent with exothermic phase separation events over 3 days at 37 °C 100% RH in the TAM. However, only the 15, 30, and 50% containing 034 samples showed pXRD patterns consistent with crystalline material in post-TAM samples. Isothermal calorimetry is a useful screening tool to probe robust SDD physical performance and help investigate the level of drug polymer miscibility under a humid stress. Orthogonal analytical techniques such as pXRD, ssNMR, and FTIR were key in this SDD formulation screening to gain physical understanding and confirm or refute whether physical changes occur during the observed thermal events characterized by the calorimetric screening experiments.

Molecular basis of crystal morphology-dependent adhesion behavior of mefenamic acid during tableting.

PURPOSE: The molecular basis of crystal surface adhesion leading to sticking was investigated by exploring the correlation of crystal adhesion to oxidized iron coated atomic force microscope (AFM) tips and bulk powder sticking behavior during tableting of two morphologically different crystals of a model drug, mefenamic acid (MA), to differences in their surface functional group orientation and energy. METHODS: MA was recrystallized into two morphologies (plates and needles) of the same crystalline form. Crystal adhesion to oxidized iron coated AFM tips and bulk powder sticking to tablet punches was assessed using a direct compression formulation. Surface functional group orientation and energies on crystal faces were modeled using Accelrys Material Studio software. RESULTS: Needle-shaped morphology showed higher sticking tendency than plates despite similar particle size. This correlated with higher crystal surface adhesion of needle-shaped morphology to oxidized iron coated AFM probe tips, and greater surface energy and exposure of polar functional groups. CONCLUSIONS: Higher surface exposure of polar functional groups correlates with higher tendency to stick to metal surfaces and AFM tips, indicating involvement of specific polar interactions in the adhesion behavior. In addition, an AFM method is identified to prospectively assess the risk of sticking during the early stages of drug development.

Diverse crystal size effects in covalent organic frameworks.

Crystal size effect is of vital importance in materials science by exerting significant influence on various properties of materials and furthermore their functions. Crystal size effect of covalent organic frameworks (COFs) has never been reported because their controllable synthesis is difficult, despite their promising properties have been exhibited in many aspects. Here, we report the diverse crystal size effects of two representative COFs based on the successful realization of crystal-size-controlled synthesis. For LZU-111 with rigid spiral channels, size effect reflects in pore surface area by influencing the pore integrity, while for flexible COF-300 with straight channels, crystal size controls structural flexibility by altering the number of repeating units, which eventually changes sorption selectivity. With the understanding and insight of the structure-property correlation not only at microscale but also at mesoscale for COFs, this research will push the COF field step forward to a significant advancement in practical applications.

Selecting and controlling API crystal form for pharmaceutical development--strategies and processes.

The success of designing, developing, manufacturing and introducing oral dosage forms of pharmaceutical products into the market relies on many steps, processes, stages and usually three phases of clinical trials. One key process is selecting an appropriate active pharmaceutical ingredient (API) crystal or amorphous form for the final dosage product: the ultimate goal of this selection process is to ensure that the manufactured product contains a stable and bioavailable active ingredient. A thorough knowledge of the solid-state chemistry of the API, the related excipients and the processes to make the product are critical in meeting this goal. Through recently published literature and the authors' experiences, this review describes the concepts and approaches that are used in the development of a truly knowledge-based crystalline API form selection process and highlights the appropriate studies which fit the Quality by Design (QbD) framework for pharmaceutical development activities. This review also discusses the potential API crystal form transformations in the API crystallization, post-crystallization and formulation stages, which are demonstrated by case study examples.

Single-crystal x-ray diffraction structures of covalent organic frameworks.

The crystallization problem is an outstanding challenge in the chemistry of porous covalent organic frameworks (COFs). Their structural characterization has been limited to modeling and solutions based on powder x-ray or electron diffraction data. Single crystals of COFs amenable to x-ray diffraction characterization have not been reported. Here, we developed a general procedure to grow large single crystals of three-dimensional imine-based COFs (COF-300, hydrated form of COF-300, COF-303, LZU-79, and LZU-111). The high quality of the crystals allowed collection of single-crystal x-ray diffraction data of up to 0.83-angstrom resolution, leading to unambiguous solution and precise anisotropic refinement. Characteristics such as degree of interpenetration, arrangement of water guests, the reversed imine connectivity, linker disorder, and uncommon topology were deciphered with atomic precision-aspects impossible to determine without single crystals.

Bioavailability enhancement of a COX-2 inhibitor, BMS-347070, from a nanocrystalline dispersion prepared by spray-drying.

Spray drying drug with excipients is usually associated with the preparation of microcrystalline or amorphous drug in order to improve bioavailability. It was found that BMS-347070, when spray-dried with Pluronic F127 from acetone or methylene chloride, was dispersed as nanosized crystalline drug within the water-soluble Pluronic matrix. The reduction in drug particle/crystallite size, coupled with wetting by the Pluronic, resulted in a fast-onset formulation with bioavailability comparable to that of a solubilized and a NanoCrystal formulation. For this system, it is theorized that the polyethylene oxide segments of Pluronic crystallize and that the polypropylene oxide segments remain amorphous, providing a size-restricted domain in which the COX-2 drug crystallizes. This results in improved bioavailability while limiting the potential risk of conversion of an amorphous drug to its crystalline state.

Low level drug product API form analysis - Avalide tablet NIR quantitative method development and robustness challenges.

Avalide(@), a medication used for the treatment of hypertension, is a combination of Irbesartan, and Hydrochlorothiazide. Irbesartan, one of the active pharmaceutical ingredients (API) in Avalide products, exists in two neat crystalline forms: Form A and Form B. Irbesartan Form A is the API form used in a wet granulation for the preparation of Avalide tablets. The presence of the less soluble Irbesartan Form B in Avalide tablets may result in the slower dissolution. In this paper, we have presented our work on the method development, verification and challenges of quantitatively detecting, via NIR and ssNMR, very small amounts of Irbesartan Form B in Avalide tablets. As part of the NIR method development and qualification, limit of detection, linearity and accuracy were examined. In addition, a limited study of the robustness of the method was conducted and a bias in the level of Form B was correlated to the ambient humidity. ssNMR, a primary method for the determination of polymorphic composition, was successfully used as an orthogonal technique to verify the accuracy of the NIR method and added to the confidence in the NIR method. The speed and efficiency of the NIR method make it a suitable and convenient tool for routine analysis of Avalide tablets for Form B in a QC environment.

Investigation of freeze/thaw-related quality attributes of a liquid biopharmaceutical formulation: the role of saccharide excipients.

Saccharides, including sucrose, trehalose, mannitol, and sorbitol, are commonly employed as stabilizers, cryoprotectants, and/or tonicity adjusters in protein formulations. During the thawing of a protein-containing formulated bulk drug substance conducted prior to a drug product (DP) filling operation, a white, crystalline precipitate was observed. In addition, upon thawing, vial breakage was observed for filled DP that had been previously frozen at -40 °C. To investigate the causes of both phenomena, the freeze/thaw behavior of the formulation components was studied. Multiple physical characterization techniques, including differential scanning calorimetry (DSC), electrical resistance measurements, thermomechanical analysis (TMA), and powder X-ray diffraction (PXRD), were utilized to characterize the formulations. The PXRD pattern of precipitate collected from thawed bulk was consistent with that of a mannitol control. An exothermic transition observed by DSC, a sharp increase in electrical resistance detected via resistivity measurements, and the onset of volumetric expansion of the frozen matrix evident in the TMA curve offer evidence that the frozen mannitol solution undergoes transitions at or near the vial breakage temperature (-22 to -23 °C) observed during warming. In addition, osmolality measurements taken from fractionated aliquots of frozen samples indicated that non-uniform concentration gradients contributed to precipitation of mannitol observed at larger scales. Small-scale laboratory experiments (i.e., 10-125 mL) failed to adequately predict behavior at larger scale (i.e., in 1 L and 2 L bottles). Upon linking the detrimental behavior to the freeze/thaw properties of the tonicity adjustor, mannitol, alternative saccharide excipients, including sorbitol, sucrose, and trehalose, were evaluated at isotonic concentrations over a temperature range of -80 to 25 °C using physical-chemical techniques and visual observation. Neither precipitation nor vial breakage was observed for the alternate saccharides. Recommendations for saccharide selection are provided based on storage conditions and scale considerations for liquid biopharmaceutical formulations. LAY ABSTRACT: Saccharides, including sucrose, trehalose, mannitol, and sorbitol, are commonly employed as stabilizers, cryoprotectants and/or tonicity adjusters in protein formulations. During thawing of formulated bulk drug substance, a white, crystalline precipitate was observed. In addition, upon thawing, vial breakage was observed for filled drug product that had been previously frozen at -40 °C. To investigate the causes of both phenomena, multiple physical characterization techniques were utilized to characterize the formulations. The powder X-ray diffraction pattern of precipitate collected from thawed bulk was consistent with that of a mannitol control. Upon linking the detrimental behavior to the freeze/thaw properties of the tonicity adjustor, mannitol, alternative saccharide excipients, including sorbitol, sucrose, and trehalose, were evaluated at isotonic concentrations over a temperature range of -80 to 25 °C using physico-chemical techniques and visual observation. Neither precipitation nor vial breakage was observed for the alternate saccharides. Recommendations for saccharide selection are given based on storage conditions and scale considerations for liquid biopharmaceutical formulations.

Amorphous drug-PVP dispersions: application of theoretical, thermal and spectroscopic analytical techniques to the study of a molecule with intermolecular bonds in both the crystalline and pure amorphous state.

We report the case of BMS-488043-PVP solid dispersions which when analysed using modulated DSC showed compliance with the Gordon-Taylor model, confirming ideal mixing behaviour of the two components. The nature or presence of stabilising interactions between drug and PVP could not be confirmed using this technique. Use of FT-IR, Raman and solid-state NMR spectroscopy confirmed the presence of stabilising hydrogen bond interactions between the drug and PVP. Similar interactions are present as intermolecular bonds in the crystalline and pure amorphous drug system. The Gordon-Taylor equation, as it is not predictive of the presence of intermolecular bonds such as hydrogen bonding in an amorphous dispersion, may underestimate the likely physical stability of solid dispersions which are produced and stabilised by these interactions.