7. Computational methods in preformulation study for pharmaceutical solid dosage forms of therapeutic proteins
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Sutapa Biswas Majee
Abstract
Design and delivery of protein-based biopharmaceuticals needs detailed planning and strict monitoring of intermediate processing steps, storage conditions and container-closure system to ensure a stable, elegant and biopharmaceutically acceptable dosage form. Selection of manufacturing process variables and conditions along with packaging specifications can be achieved through properly designed preformulation study protocol for the formulation. Thermodynamic stability and biological activity of therapeutic proteins depend on folding-unfolding and threedimensional packing dynamics of amino acid network in the protein molecule. Lack of favourable environment may cause protein aggregation with loss in activity and even fatal immunological reaction. Although lyophilization can enhance the stability of protein-based formulations in the solid state, it can induce protein unfolding leading to thermodynamic instability. Formulation stabilizers such as preservatives can also result in aggregation of therapeutic proteins. Modern instrumental techniques in conjunction with computational tools enable rapid and accurate prediction of amino acid sequence, thermodynamic parameters associated with protein folding and detection of aggregation “hot-spots.” Globular proteins pose a challenge during investigations on their aggregation propensity. Biobetter therapeutic monoclonal antibodies with enhanced stability, solubility and reduced immunogenic potential can be designed through mutation of aggregation-prone zones. The objective of the present review article is to focus on the various analytical methods and computational approaches used in the study of thermodynamic stability and aggregation tendency of therapeutic proteins, with an aim to develop optimal and marketable formulation. Knowledge of protein dynamics through application of computational tools will provide the essential inputs and relevant information for successful and meaningful completion of preformulation studies on solid dosage forms of therapeutic proteins.
Abstract
Design and delivery of protein-based biopharmaceuticals needs detailed planning and strict monitoring of intermediate processing steps, storage conditions and container-closure system to ensure a stable, elegant and biopharmaceutically acceptable dosage form. Selection of manufacturing process variables and conditions along with packaging specifications can be achieved through properly designed preformulation study protocol for the formulation. Thermodynamic stability and biological activity of therapeutic proteins depend on folding-unfolding and threedimensional packing dynamics of amino acid network in the protein molecule. Lack of favourable environment may cause protein aggregation with loss in activity and even fatal immunological reaction. Although lyophilization can enhance the stability of protein-based formulations in the solid state, it can induce protein unfolding leading to thermodynamic instability. Formulation stabilizers such as preservatives can also result in aggregation of therapeutic proteins. Modern instrumental techniques in conjunction with computational tools enable rapid and accurate prediction of amino acid sequence, thermodynamic parameters associated with protein folding and detection of aggregation “hot-spots.” Globular proteins pose a challenge during investigations on their aggregation propensity. Biobetter therapeutic monoclonal antibodies with enhanced stability, solubility and reduced immunogenic potential can be designed through mutation of aggregation-prone zones. The objective of the present review article is to focus on the various analytical methods and computational approaches used in the study of thermodynamic stability and aggregation tendency of therapeutic proteins, with an aim to develop optimal and marketable formulation. Knowledge of protein dynamics through application of computational tools will provide the essential inputs and relevant information for successful and meaningful completion of preformulation studies on solid dosage forms of therapeutic proteins.
Chapters in this book
- Frontmatter i
- Preface of the Book of Proceedings of the Virtual Conference on Computational Science (VCCS-2016) v
- Contents vii
- List of contributing authors xi
- 1. Addressing the challenges of standalone multi-core simulations in molecular dynamics 1
- 2. Optical and magnetic properties of free-standing silicene, germanene and T-graphene system 23
- 3. Theoretical study of the electronic states of newly detected dications. Case of MgS2+ AND SiN2+ 71
- 4. Analytical Solution of Pantograph Equation with Incommensurate Delay 93
- 5. Computational chemistry applied to vibrational spectroscopy: A tool for characterization of nucleic acid bases and some of their 5-substituted derivatives 117
- 6. Mechanism of nucleophilic substitution reactions of 4-(4’-nitro)phenylnitrobenzofurazan ether with aniline in acetonitrile 153
- 7. Computational methods in preformulation study for pharmaceutical solid dosage forms of therapeutic proteins 163
- 8. Computational Investigation of Cationic, Anionic and Neutral Ag2AuN (N = 1–7) Nanoalloy Clusters 173
- 9. Evacuation simulation using Hybrid Space Discretisation and Application to Large Underground Rail Tunnel Station 191
- 10. DFT study of anthocyanidin and anthocyanin pigments for Dye-Sensitized Solar Cells: Electron injecting from the excited states and adsorption onto TiO2 (anatase) surface 205
- 11. Elemental Two-Dimensional Materials Beyond Graphene 219
- Index 229
Chapters in this book
- Frontmatter i
- Preface of the Book of Proceedings of the Virtual Conference on Computational Science (VCCS-2016) v
- Contents vii
- List of contributing authors xi
- 1. Addressing the challenges of standalone multi-core simulations in molecular dynamics 1
- 2. Optical and magnetic properties of free-standing silicene, germanene and T-graphene system 23
- 3. Theoretical study of the electronic states of newly detected dications. Case of MgS2+ AND SiN2+ 71
- 4. Analytical Solution of Pantograph Equation with Incommensurate Delay 93
- 5. Computational chemistry applied to vibrational spectroscopy: A tool for characterization of nucleic acid bases and some of their 5-substituted derivatives 117
- 6. Mechanism of nucleophilic substitution reactions of 4-(4’-nitro)phenylnitrobenzofurazan ether with aniline in acetonitrile 153
- 7. Computational methods in preformulation study for pharmaceutical solid dosage forms of therapeutic proteins 163
- 8. Computational Investigation of Cationic, Anionic and Neutral Ag2AuN (N = 1–7) Nanoalloy Clusters 173
- 9. Evacuation simulation using Hybrid Space Discretisation and Application to Large Underground Rail Tunnel Station 191
- 10. DFT study of anthocyanidin and anthocyanin pigments for Dye-Sensitized Solar Cells: Electron injecting from the excited states and adsorption onto TiO2 (anatase) surface 205
- 11. Elemental Two-Dimensional Materials Beyond Graphene 219
- Index 229
