Formulation science

Gaithersburg, MD, United States

Formulation science

Gaithersburg, MD, United States
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Nie H.,Formulation science | Byrn S.R.,Purdue University | Zhou Q.T.,Purdue University
Drug Development and Industrial Pharmacy | Year: 2017

Using pharmaceutical salts in solid dosage forms can raise stability concerns, especially salt dissociation which can adversely affect the product performance. Therefore, a thorough understanding of the salt instability encountered in solid-state formulations is imperative to ensure the product quality. The present article uses the fundamental theory of acid base, ionic equilibrium, relationship of pH and solubility as a starting point to illustrate and interpret the salt formation and salt disproportionation in pharmaceutical systems. The criteria of selecting the optimal salt form and the underlying theory of salt formation and disproportionation are reviewed in detail. Factors influencing salt stability in solid dosage forms are scrutinized and discussed with the case studies. In addition, both commonly used and innovative strategies for preventing salt dissociations in formulation, on storage and during manufacturing will be suggested herein. This article will provide formulation scientists and manufacturing engineers an insight into the mechanisms of salt disproportionation and salt formation, which can help them to avoid and solve the instability issues of pharmaceutical salts in the product design. © 2017 Informa UK Limited, trading as Taylor & Francis Group


Muralidhara B.K.,Formulation science | Baid R.,Formulation science | Bishop S.M.,Formulation science | Huang M.,Pfizer | And 2 more authors.
Drug Discovery Today | Year: 2016

Protein expression therapy using nucleic acid macromolecules (NAMs) as a new paradigm in medicine has recently gained immense therapeutic potential. With the advancement of nonviral delivery it has been possible to target NAMs against cancer, immunodeficiency and infectious diseases. Owing to the complex and fragile structure of NAMs, however, development of a suitable, stable formulation for a reasonable product shelf-life and efficacious delivery is indeed challenging to achieve. This review provides a synopsis of challenges in the formulation and stability of DNA/m-RNA based medicines and probable mitigation strategies including a brief summary of delivery options to the target cells. Nucleic acid based drugs at various stages of ongoing clinical trials are compiled. © 2016 Published by Elsevier Ltd.


Cash P.W.,Analytical Biotechnology | Narwal R.,Formulation science | Levitskaya S.V.,Analytical Biotechnology | Krause S.,Analytical Biotechnology | Mazaheri M.,Analytical Biotechnology
PDA Journal of Pharmaceutical Science and Technology | Year: 2016

Visible particles must be monitored as part of the control strategy for pharmaceutical products. Extraneous (foreign) particles are not acceptable in parenteral drug products. In biopharmaceuticals, formation of protein particles is recognized as an inherent quality attribute. All protein therapeutics contain particles that vary greatly in visibility and size from invisible (sub-micron) to visible (millimeter) and, as part of the control strategy, biopharmaceutical companies are required to monitor and minimize the presence of visible and sub-visible particles in their products. There is an industry-wide unmet need for particle standards for visual inspection of protein therapeutics. A new, semi-quantitative method using particle standards for assessing the levels of small, inherent visible particles is presented. This method can be used during product development to identify a formulation that minimizes particle formation and also during release and stability testing to monitor and control inherent proteinaceous visible particles. © PDA, Inc. 2016.


Taraban M.B.,University of Maryland, Baltimore | Depaz R.A.,Formulation science | Lobo B.,Formulation science | Yu Y.B.,University of Maryland, Baltimore
Analytical Chemistry | Year: 2017

Formulation stability is a critical attribute of any protein-based biopharmaceutical drug due to a protein's inherent tendency to aggregate. Advanced analytical techniques currently used for characterization of protein aggregates are prone to a number of limitations and usually require additional manipulations with the sample, such as dilution, separation, labeling, and use of special cuvettes. In the present work, we compared conventional techniques for the analysis of protein aggregates with a novel approach that employs the water proton transverse relaxation rate R2(1H2O). We explored differences in the sensitivity of conventional techniques, size-exclusion chromatography (SEC), microflow imaging (MFI), and dynamic light scattering (DLS), and water NMR (wNMR) toward the presence of monoclonal antibody aggregates generated by different stresses. We demonstrate that wNMR outperformed SEC, DLS, and MFI in that it was most consistently sensitive to increases in both soluble and insoluble aggregates, including subvisible particles. The simplicity of wNMR, its sensitivity, and possibility of noninvasive measurements are unique advantages that would permit its application for more efficient and higher throughput optimization of protein formulations. © 2017 American Chemical Society.


Gerhardt A.,University of Colorado at Boulder | McGraw N.R.,University of Colorado at Boulder | Schwartz D.K.,University of Colorado at Boulder | Bee J.S.,Formulation science | And 2 more authors.
Journal of Pharmaceutical Sciences | Year: 2014

The stability of therapeutic proteins formulated in prefilled syringes (PFS) may be negatively impacted by the exposure of protein molecules to silicone oil-water interfaces and air-water interfaces. In addition, agitation, such as that experienced during transportation, may increase the detrimental effects (i.e., protein aggregation and particle formation) of protein interactions with interfaces. In this study, surfactant-free formulations containing either a monoclonal antibody or lysozyme were incubated in PFS, where they were exposed to silicone oil-water interfaces (siliconized syringe walls), air-water interfaces (air bubbles), and agitation stress (occurring during end-over-end rotation). Using flow microscopy, particles (≥2 μm diameter) were detected under all conditions. The highest particle concentrations were found in agitated, siliconized syringes containing an air bubble. The particles formed in this condition consisted of silicone oil droplets and aggregated protein, as well as agglomerates of protein aggregates and silicone oil. We propose an interfacial mechanism of particle generation in PFS in which capillary forces at the three-phase (silicone oil-water-air) contact line remove silicone oil and gelled protein aggregates from the interface and transport them into the bulk. This mechanism explains the synergistic effects of silicone oil-water interfaces, air-water interfaces, and agitation in the generation of particles in protein formulations. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.


Zhou Q.,University of Minnesota | Zhou Q.,Huazhong University of Science and Technology | Shi L.,University of Minnesota | Marinaro W.,Formulation science | And 2 more authors.
Powder Technology | Year: 2013

Using a representative powder blend containing ibuprofen, the applicability of coating with silica nanoparticles using a dry comilling process to effectively enhance flowability of formulated pharmaceutical powders was investigated. Using a shear cell, we systematically studied effects of process parameters, including the total number of comilling cycles, silica loading level, type of screen (mesh size), impeller speed, and impeller type, on the efficiency of the nanocoating process. Impact of silica coating on powder tabletability was also assessed using a compaction simulator. Results confirm that coating with silica nano particles significantly improves flowability of the formulated ibuprofen blend. The two most prominent factors that lead to flowability improvement are 1) repeated comilling cycles and 2) higher silica loading. In addition, we have observed that simple blending is effective in coating silica nanoparticles to improve flowability of the formulated ibuprofen powders, which is not very cohesive. This suggests the possibility of improving flowability of a sub-optimum formulation by prolonging the blending process in presence of colloidal silica. Moreover, silica coated ibuprofen blend exhibits improved tabletability and compactibility without significantly impacting compressibility. The simultaneous improvement in powder tabletability and flowability shows the potential of the nanocoating strategy in improving tablet manufacturability of pharmaceutical powders. © 2013 Elsevier B.V.


Li C.H.,Amgen Inc. | Narhi L.O.,Amgen Inc. | Wen J.,Amgen Inc. | Dimitrova M.,Formulation science | And 6 more authors.
Biochemistry | Year: 2012

The circulation half-life of a potential therapeutic can be increased by fusing the molecule of interest (an active peptide, the extracellular domain of a receptor, an enzyme, etc.) to the Fc fragment of a monoclonal antibody. For the fusion protein to be a successful therapeutic, it must be stable to process and long-term storage conditions, as well as to physiological conditions. The stability of the Fc used is critical for obtaining a successful therapeutic protein. The effects of pH, temperature, and salt on the stabilities of Escherichia coli- and Chinese hamster ovary cell (CHO)-derived IgG1 Fc high-order structure were probed using a variety of biophysical techniques. Fc molecules derived from both E. coli and CHO were compared. The IgG1 Fc molecules from both sources (glycosylated and aglycosylated) are folded at neutral pH and behave similarly upon heat- and low pH-induced unfolding. The unfolding of both IgG1 Fc molecules occurs via a multistep unfolding process, with the tertiary structure and CH2 domain unfolding first, followed by changes in the secondary structure and CH3 domain. The acid-induced unfolding of IgG1 Fc molecules is only partially reversible, with the formation of high-molecular weight species. The CHO-derived Fc protein (glycosylated) is more compact (smaller hydrodynamic radius) than the E. coli-derived protein (aglycosylated) at neutral pH. Unfolding is dependent on pH and salt concentration. The glycosylated CH2 domain melts at a temperature 4-5 C higher than that of the aglycosylated domain, and the low-pH-induced unfolding of the glycosylated Fc molecule occurs at a pH ∼0.5 pH unit lower than that of the aglycosylated protein. The difference observed between E. coli- and CHO-derived Fc molecules primarily involves the CH2 domain, where the glycosylation of the Fc resides. © 2012 American Chemical Society.


PubMed | Formulation science and Drug Delivery and Device Development
Type: | Journal: Journal of pharmaceutical sciences | Year: 2016

It is vital to understand the impact of transportation on monoclonal antibody (mAb) product quality during drug product development. Fully representative real-time shipment studies are resource intensive, so in this work, we studied laboratory agitation methods to mimic the effect of real-time shipment on aggregation, specifically subvisible particle formation. The agitation methods studied include a rotator, orbital shaker, vortexer, and shipping simulator vibration table. The simulator is able to predict the particle formation behavior during real-time shipment for a number of mAbs in vial and prefilled syringe configurations, with a correlation of about 90%, whereas the other methods of agitation were inconsistent. This study demonstrates that using a shipping simulator vibration table provides an opportunity for consistent and predictive development studies of shipping stress with minimal resource requirements during early- or late-stage drug product development.


PubMed | Formulation science, MedImmune Ltd. and University of Cambridge
Type: Journal Article | Journal: Journal of the American Chemical Society | Year: 2016

Aggregation and amyloid fibril formation of peptides and proteins is a widespread phenomenon. It has serious implications in a range of areas from biotechnological and pharmaceutical applications to medical disorders. The aim of this study was to develop a better understanding of the mechanism of aggregation and amyloid fibrillation of an important pharmaceutical, human glucagon-like peptide-1 (GLP-1). GLP-1 is a 31-residue hormone peptide that plays an important role regulating blood glucose levels, analogues of which are used for treatment of type 2 diabetes. Amyloid fibril formation of GLP-1 was monitored using thioflavin T fluorescence as a function of peptide concentration between pH 7.5 and 8.2. Results from these studies establish that there is a highly unusual pH-induced switch in GLP-1 aggregation kinetics. At pH 8.2, the kinetics are consistent with a nucleation-polymerization mechanism for fibril formation. However, at pH 7.5, highly unusual kinetics are observed, where the lag time increases with increasing peptide concentration. We attribute this result to the formation of off-pathway species together with an initial slow, unimolecular step where monomer converts to a different monomeric form that forms on-pathway oligomers and ultimately fibrils. Estimation of the pK


PubMed | Formulation science and Analytical Biotechnology
Type: Journal Article | Journal: PDA journal of pharmaceutical science and technology | Year: 2016

Visible particles must be monitored as part of the control strategy for pharmaceutical products. Extraneous (foreign) particles are not acceptable in parenteral drug products. In biopharmaceuticals, formation of protein particles is recognized as an inherent quality attribute. All protein therapeutics contain particles that vary greatly in visibility and size from invisible (sub-micron) to visible (millimeter) and, as part of the control strategy, biopharmaceutical companies are required to monitor and minimize the presence of visible and sub-visible particles in their products. There is an industry-wide unmet need for particle standards for visual inspection of protein therapeutics. A new, semi-quantitative method using particle standards for assessing the levels of small, inherent visible particles is presented. This method can be used during product development to identify a formulation that minimizes particle formation and also during release and stability testing to monitor and control inherent proteinaceous visible particles.Visible particles must be monitored as part of the control strategy for parenteral biopharmaceutical drug products. In these products, formation of protein particles is a natural occurrence. All protein drugs contain particles that vary greatly in visibility and size from invisible (sub-micron) to visible (millimeter), and pharmaceutical companies are required to monitor and minimize the presence of visible and sub-visible particles in their products. There is an industry-wide unmet need for particle standards for visual inspection of protein drugs. A new, semi-quantitative method using particle standards for assessing the levels of small, naturally occurring visible particles is presented. This method can be used during drug development to identify a formulation that minimizes particle formation and also during testing of final clinical or commercial drug product to monitor and control naturally occurring proteinaceous visible particles.

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