Co-micronization: innovative technology to enhance oral
bioavailability of poorly water soluble APIs.
Jerome HECQ, Pharm.D, Ph.D.
APGI Day – MERCK and GATTEFOSSE
CNAM – Paris
24th May 2016
Micronization - Solubility Enhancement by MicronizationSagar Savale
Micronization is a technique used to reduce particle size to less than 10 microns in order to enhance drug solubility and bioavailability. It involves accelerating drug particles through impacts with other particles or solid surfaces using techniques like jet milling or rotor stator colloid mills. The document discusses various methods of micronization including ball milling, high pressure homogenization, and supercritical fluid processes. It provides examples of how these techniques work and notes that micronization is useful for improving solubility of poorly water soluble drugs.
Discussed Micronization as a vital unit operation process for particle size reduction and improvement in solubility parameters of poorly water soluble drugs.
The document discusses granulation as a process to combine particles into larger masses for improved flow and compression characteristics. It defines granulation and describes the objective of combining ingredients to produce quality tablets. Various techniques for granulation like wet and dry granulation are discussed along with common equipment used like fluid bed granulators, Littleford loaders, and Diosna mixers. Granule characteristics and factors affecting granulation are also summarized.
This document discusses tablet coating defects, their causes, and remedies. It begins with an introduction to tablet coating and why it is done. Common coating defects are then described such as blistering, cratering, pitting, blooming, blushing, orange peel, sticking, picking, color variation, bridging, erosion, and twinning. The causes and remedies for each defect are provided. Critical parameters for successful tablet coating are also listed, including nozzle spacing, spray pattern, spray speed, droplet size, drying temperature, and air speed. References on tablet coating and manufacturing defects are included at the end.
This document provides an overview of fast dissolving oral thin films (FDOTF). It begins with an introduction describing FDOTFs as thin polymeric strips that dissolve quickly in the mouth without water. The document then covers special features of FDOTFs, compares them to fast dissolving tablets, and describes their mechanism of action, classifications, properties, advantages, disadvantages, formulations, manufacturing methods, evaluation, and concludes with references.
The document discusses key concepts and steps in preformulation testing. Preformulation involves investigating the physical and chemical properties of a drug substance alone and when combined with excipients. This generates useful information for formulating stable and safe dosage forms with good bioavailability. Some important properties discussed include solubility, particle size and shape, melting point, thermal analysis profile, hygroscopicity, and polymorphism potential. Determining these properties of a new drug substance is an important first step before developing drug formulations.
In this slide contains introduction, copmpression, consolidation, compaction, heckel plots and equation, interpretation and application.
Presented by: NARAYAN SINGH UDIT (Department of pharmaceutics).
RIPER, anantapur
1) The document describes the preparation and evaluation of sustained release microparticles of the drug norfloxacin using an ionotropic gelation technique.
2) Three formulations were prepared varying the concentration of calcium chloride to investigate its effect on drug entrapment efficiency, swelling, and in vitro drug release.
3) Formulation A2, prepared with 2% w/v calcium chloride, showed the highest drug entrapment efficiency of 54.84% and provided the most sustained drug release over 5 hours of 40.51% compared to the other formulations.
Micronization - Solubility Enhancement by MicronizationSagar Savale
Micronization is a technique used to reduce particle size to less than 10 microns in order to enhance drug solubility and bioavailability. It involves accelerating drug particles through impacts with other particles or solid surfaces using techniques like jet milling or rotor stator colloid mills. The document discusses various methods of micronization including ball milling, high pressure homogenization, and supercritical fluid processes. It provides examples of how these techniques work and notes that micronization is useful for improving solubility of poorly water soluble drugs.
Discussed Micronization as a vital unit operation process for particle size reduction and improvement in solubility parameters of poorly water soluble drugs.
The document discusses granulation as a process to combine particles into larger masses for improved flow and compression characteristics. It defines granulation and describes the objective of combining ingredients to produce quality tablets. Various techniques for granulation like wet and dry granulation are discussed along with common equipment used like fluid bed granulators, Littleford loaders, and Diosna mixers. Granule characteristics and factors affecting granulation are also summarized.
This document discusses tablet coating defects, their causes, and remedies. It begins with an introduction to tablet coating and why it is done. Common coating defects are then described such as blistering, cratering, pitting, blooming, blushing, orange peel, sticking, picking, color variation, bridging, erosion, and twinning. The causes and remedies for each defect are provided. Critical parameters for successful tablet coating are also listed, including nozzle spacing, spray pattern, spray speed, droplet size, drying temperature, and air speed. References on tablet coating and manufacturing defects are included at the end.
This document provides an overview of fast dissolving oral thin films (FDOTF). It begins with an introduction describing FDOTFs as thin polymeric strips that dissolve quickly in the mouth without water. The document then covers special features of FDOTFs, compares them to fast dissolving tablets, and describes their mechanism of action, classifications, properties, advantages, disadvantages, formulations, manufacturing methods, evaluation, and concludes with references.
The document discusses key concepts and steps in preformulation testing. Preformulation involves investigating the physical and chemical properties of a drug substance alone and when combined with excipients. This generates useful information for formulating stable and safe dosage forms with good bioavailability. Some important properties discussed include solubility, particle size and shape, melting point, thermal analysis profile, hygroscopicity, and polymorphism potential. Determining these properties of a new drug substance is an important first step before developing drug formulations.
In this slide contains introduction, copmpression, consolidation, compaction, heckel plots and equation, interpretation and application.
Presented by: NARAYAN SINGH UDIT (Department of pharmaceutics).
RIPER, anantapur
1) The document describes the preparation and evaluation of sustained release microparticles of the drug norfloxacin using an ionotropic gelation technique.
2) Three formulations were prepared varying the concentration of calcium chloride to investigate its effect on drug entrapment efficiency, swelling, and in vitro drug release.
3) Formulation A2, prepared with 2% w/v calcium chloride, showed the highest drug entrapment efficiency of 54.84% and provided the most sustained drug release over 5 hours of 40.51% compared to the other formulations.
Pelletization involves agglomerating powders into small spherical units called pellets. It differs from granulation in producing smaller, more uniform pellets. Common pelletization techniques include extrusion-spheronization, dry powder layering, fluid bed processes, and spray drying or congealing of solutions or suspensions. Pellets offer benefits like uniform content, preventing dust formation, and enabling controlled release when coated. Extrusion-spheronization involves extruding mixes through screens then spheronizing on a rotating friction disk. Process factors like disk speed and groove pattern affect pellet formation. Fluid bed processes spray binders onto powders for granulation and pelletization.
This document summarizes a seminar on drug excipient compatibility studies, which are an important part of preformulation studies. It defines incompatibility and the different types. The objectives and aspects of compatibility tests are discussed. The key steps in a compatibility study including sample preparation, storage conditions, and analytical techniques are outlined. Specific techniques like DSC and TLC are described along with examples. Common known incompatibilities between functional groups and specific excipients are listed. The importance of excipient impurities and compatibility studies for different dosage forms like aerosols and parenterals is highlighted.
Factors affecting protein drug binding and rotein drug bindingAshwani Kumar Singh
Factors that can affect protein-drug binding include drug properties, protein properties, drug interactions, and patient characteristics. Drug properties like lipophilicity, concentration, and affinity determine binding, while protein concentration and binding sites influence binding. Drug interactions can occur via competition for binding sites or with normal constituents. Patient age, genetic variations, and disease states can also impact binding by altering protein levels.
Presentation describes on reasons to conduct stability studies, effect of physical and chemical drug decomposition, effect of light and temperature on drug decomposition and storage of drug
This document summarizes a presentation on powder compression. It discusses properties related to powder compression like angle of repose and Carr's index. It describes the compression cycle and forces involved like frictional and distributional forces. Equations related to compression are also presented, like the Heckel and Kawakita equations. The conclusion restates that powder compression involves reduction in volume through application of force.
The document discusses key topics in powder compression:
1. Compression properties like compressibility and compactibility are important for forming tablets.
2. Axial and radial forces are exerted during compression and must be withstood for decompression.
3. The compression process involves stages like particle rearrangement, deformation, fragmentation, and bonding which increase density and form strong tablets.
This document discusses drug transporters and their role in drug absorption, distribution, metabolism and excretion. It covers the main types of transporters including ABC transporters like P-glycoprotein and SLC transporters. It describes how transporters regulate the movement of drugs across membranes in organs like the intestine, liver and kidneys. It also discusses how overexpression of transporters like P-glycoprotein can lead to multidrug resistance and the various approaches used to overcome resistance, such as inhibitors of transporter activity.
Granulation is the process of binding particles together to form larger granules. There are two main types: dry granulation which uses no liquid, and wet granulation which uses a liquid binding solution. Wet granulation methods include fluidized bed granulation where granulation and drying occur together, tumbling granulation using drums or pans where particles are set in motion by tumbling forces, and mixer-granulators which use high shear mixing to form agglomerates. Key steps in wet granulation are wetting, nucleation and binder distribution, consolidation and growth, and attrition and breakage. Granule size and properties depend on the specific granulation equipment used.
Bilayer tablets can avoid chemical incompatibilities between active pharmaceutical ingredients (APIs) through physical separation of layers, allowing different release profiles like immediate and extended release. Key advantages include combining incompatible drugs, reducing pill burden through additive drug effects, and addressing co-morbid conditions with a single tablet. Bilayer tablets are useful for APIs with short half-lives, instability at intestinal pH, or high first-pass metabolism. Practical challenges in developing bilayer tablets include layer separation, determining layer order and ratios, and cross-contamination between layers.
This document discusses compression and consolidation in pharmaceutical manufacturing. It defines compression, consolidation, and compaction. It describes the fundamentals of powder compression including attractive forces between particles. It discusses derived parameters such as solid-air interface, angle of repose, mass-volume relationships, density, and compressibility. It also describes methods for powder compression like direct compression, dry granulation, and wet granulation. Finally, it discusses compression machines and their components.
This document summarizes a seminar on biodegradable and non-biodegradable polymers. It introduces polymers and describes biodegradable polymers as those that can degrade in biological fluids over time, releasing dissolved drugs. It outlines some advantages of biodegradable polymers like sustained drug delivery and disadvantages like burst release. The document classifies polymers as biodegradable or non-biodegradable and describes factors that affect biodegradation rates. Examples of synthetic and natural biodegradable polymers are provided, such as polyglycolic acid, collagen, starch and chitosan.
The document discusses common problems encountered in tablet manufacturing including capping, lamination, cracking, chipping, sticking, picking, binding, and double impression. For each problem, the document defines it, identifies potential causes related to the formulation or manufacturing process/machine, and provides remedies. It also discusses defects that can occur during tablet coating like picking, sticking, twinning, color variation, orange peel, roughness, bridging, blistering, erosion, and peeling/frosting.
This document discusses rheology, which is the science describing the flow and deformation of matter under stress. It defines key terms like viscosity, shear stress, shear rate, and classifies fluids as Newtonian or non-Newtonian based on their relationship between shear stress and shear rate. Newtonian fluids have a constant viscosity regardless of shear rate, while non-Newtonian fluids have variable viscosity. Plastic, pseudoplastic, and dilatant behaviors are described for non-Newtonian fluids. Thixotropy, which is a time-dependent decrease and recovery of viscosity under shear, is also discussed. The document concludes by explaining the operation and calibration of common viscometers.
This document discusses various techniques to improve the solubility of poorly soluble drugs, which is important for developing effective dosage forms and achieving desired drug concentrations. It defines solubility and discusses the importance of solubility in drug development. Some key techniques covered are co-solvency, use of surfactants, solid dispersions, complexation, changing temperature, hydrotropy, polymorphism, amorphous forms, solvates, salt formation, and micronization/nanonization. The goal is to select the optimal method for a given drug to enhance dissolution and absorption.
This presentation discusses roller compactors, which are used to press powders into solid compacts like flakes or sheets. Key factors that affect roller compaction include compaction pressure, feeding screw speed, and roll speed. A roller compactor generally consists of a feeding system, compaction unit with counter-rotating rolls, and a size reduction unit. It works by applying force between the rolls to compact powders into a ribbon. Roller compactors can have either a fixed or floating gap between rolls. The major advantages include avoiding solvents, suitability for heat-sensitive compounds, and producing porous tablets for improved dissolution. Applications in pharmaceuticals include excipient production, drug compaction, herbal extract granulation, and
Tablets are one of the most common oral solid dosage forms. They can be produced through compression or molding methods. There are several types of tablets including compressed, sugar-coated, film-coated, enteric-coated, and controlled-release tablets. Tablets contain active drug ingredients along with excipients that serve various purposes like diluents, binders, lubricants, disintegrants, and colors. Excipients are carefully selected to provide tablets with properties like hardness, disintegration, and appropriate dissolution for drug release.
This document provides an overview of a seminar presentation on drug stability given by Ms. Swati S. Bharati to Mumbai University. The presentation covers topics such as the importance of stability testing, degradation pathways including physical, chemical and microbial degradation, kinetic stability, and solution and solid state stability. It defines stability and the purpose of stability studies. Examples are provided to illustrate different types of degradation pathways and how they can be prevented.
Direct compression is the most advanced technology. It involves only blending and compression. Thus offering advantage particularly in terms of speedy production. Because it requires fewer unit operations, less machinery, reduced number of personnel and considerably less processing time along with increased product stability.
Hot melt extrusion with PVA – solubility enhancement, supersaturation perform...MilliporeSigma
Hot melt extrusion has successfully emerged as an innovative manufacturing technology in pharmaceutical industry for the creation of amorphous solid dispersions (ASDs).
In this webinar you will learn about the potential of hot melt extrusion to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA) as a matrix polymer. We will provide an overview about different types of solid dispersions and their evolution in the pharmaceutical field. A brief introduction in hot melt extrusion processing will be given as well as actual formulation trends. You will get insights in potential down-stream options to create your final dosage form and you will gain ideas on how to speed up your formulation development.
A detailed background of PVA will be provided including its physical properties as well as its regulatory status. PVA is more than a polymer. Due to its amphiphilic structure it has the potential to improve the supersaturation of low soluble APIs and to prevent precipitation after release. This highlights the versatility of PVA as an advanced polymer for HME applications and we will guide you through our latest research activities so that you can leverage our knowledge to improve your formulations.
This webinar includes:
- The current status and further potential of HME in pharmaceutical industry
- Advantages of PVA in the field of ASDs: Solubility improvement, impact on supersaturation potential, stability data generated on sample formulations & downstream options
- Deep dive into latest research activities: Permeation studies with Caco-2 cell membranes, pH shift studies to investigate supersaturation potential, ongoing research activities to get to know a more detailed understanding of matrix systems and their intermolecular interactions
In this webinar, you will learn:
- which potential hot melt extrusion has, to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA)
- why PVA is more than just a polymer
- how to create your final dosage form and speed up your formulation development
Hot melt extrusion with PVA – solubility enhancement, supersaturation perform...Merck Life Sciences
Hot melt extrusion has successfully emerged as an innovative manufacturing technology in pharmaceutical industry for the creation of amorphous solid dispersions (ASDs).
In this webinar you will learn about the potential of hot melt extrusion to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA) as a matrix polymer. We will provide an overview about different types of solid dispersions and their evolution in the pharmaceutical field. A brief introduction in hot melt extrusion processing will be given as well as actual formulation trends. You will get insights in potential down-stream options to create your final dosage form and you will gain ideas on how to speed up your formulation development.
A detailed background of PVA will be provided including its physical properties as well as its regulatory status. PVA is more than a polymer. Due to its amphiphilic structure it has the potential to improve the supersaturation of low soluble APIs and to prevent precipitation after release. This highlights the versatility of PVA as an advanced polymer for HME applications and we will guide you through our latest research activities so that you can leverage our knowledge to improve your formulations.
This webinar includes:
- The current status and further potential of HME in pharmaceutical industry
- Advantages of PVA in the field of ASDs: Solubility improvement, impact on supersaturation potential, stability data generated on sample formulations & downstream options
- Deep dive into latest research activities: Permeation studies with Caco-2 cell membranes, pH shift studies to investigate supersaturation potential, ongoing research activities to get to know a more detailed understanding of matrix systems and their intermolecular interactions
In this webinar, you will learn:
- which potential hot melt extrusion has, to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA)
- why PVA is more than just a polymer
- how to create your final dosage form and speed up your formulation development
Pelletization involves agglomerating powders into small spherical units called pellets. It differs from granulation in producing smaller, more uniform pellets. Common pelletization techniques include extrusion-spheronization, dry powder layering, fluid bed processes, and spray drying or congealing of solutions or suspensions. Pellets offer benefits like uniform content, preventing dust formation, and enabling controlled release when coated. Extrusion-spheronization involves extruding mixes through screens then spheronizing on a rotating friction disk. Process factors like disk speed and groove pattern affect pellet formation. Fluid bed processes spray binders onto powders for granulation and pelletization.
This document summarizes a seminar on drug excipient compatibility studies, which are an important part of preformulation studies. It defines incompatibility and the different types. The objectives and aspects of compatibility tests are discussed. The key steps in a compatibility study including sample preparation, storage conditions, and analytical techniques are outlined. Specific techniques like DSC and TLC are described along with examples. Common known incompatibilities between functional groups and specific excipients are listed. The importance of excipient impurities and compatibility studies for different dosage forms like aerosols and parenterals is highlighted.
Factors affecting protein drug binding and rotein drug bindingAshwani Kumar Singh
Factors that can affect protein-drug binding include drug properties, protein properties, drug interactions, and patient characteristics. Drug properties like lipophilicity, concentration, and affinity determine binding, while protein concentration and binding sites influence binding. Drug interactions can occur via competition for binding sites or with normal constituents. Patient age, genetic variations, and disease states can also impact binding by altering protein levels.
Presentation describes on reasons to conduct stability studies, effect of physical and chemical drug decomposition, effect of light and temperature on drug decomposition and storage of drug
This document summarizes a presentation on powder compression. It discusses properties related to powder compression like angle of repose and Carr's index. It describes the compression cycle and forces involved like frictional and distributional forces. Equations related to compression are also presented, like the Heckel and Kawakita equations. The conclusion restates that powder compression involves reduction in volume through application of force.
The document discusses key topics in powder compression:
1. Compression properties like compressibility and compactibility are important for forming tablets.
2. Axial and radial forces are exerted during compression and must be withstood for decompression.
3. The compression process involves stages like particle rearrangement, deformation, fragmentation, and bonding which increase density and form strong tablets.
This document discusses drug transporters and their role in drug absorption, distribution, metabolism and excretion. It covers the main types of transporters including ABC transporters like P-glycoprotein and SLC transporters. It describes how transporters regulate the movement of drugs across membranes in organs like the intestine, liver and kidneys. It also discusses how overexpression of transporters like P-glycoprotein can lead to multidrug resistance and the various approaches used to overcome resistance, such as inhibitors of transporter activity.
Granulation is the process of binding particles together to form larger granules. There are two main types: dry granulation which uses no liquid, and wet granulation which uses a liquid binding solution. Wet granulation methods include fluidized bed granulation where granulation and drying occur together, tumbling granulation using drums or pans where particles are set in motion by tumbling forces, and mixer-granulators which use high shear mixing to form agglomerates. Key steps in wet granulation are wetting, nucleation and binder distribution, consolidation and growth, and attrition and breakage. Granule size and properties depend on the specific granulation equipment used.
Bilayer tablets can avoid chemical incompatibilities between active pharmaceutical ingredients (APIs) through physical separation of layers, allowing different release profiles like immediate and extended release. Key advantages include combining incompatible drugs, reducing pill burden through additive drug effects, and addressing co-morbid conditions with a single tablet. Bilayer tablets are useful for APIs with short half-lives, instability at intestinal pH, or high first-pass metabolism. Practical challenges in developing bilayer tablets include layer separation, determining layer order and ratios, and cross-contamination between layers.
This document discusses compression and consolidation in pharmaceutical manufacturing. It defines compression, consolidation, and compaction. It describes the fundamentals of powder compression including attractive forces between particles. It discusses derived parameters such as solid-air interface, angle of repose, mass-volume relationships, density, and compressibility. It also describes methods for powder compression like direct compression, dry granulation, and wet granulation. Finally, it discusses compression machines and their components.
This document summarizes a seminar on biodegradable and non-biodegradable polymers. It introduces polymers and describes biodegradable polymers as those that can degrade in biological fluids over time, releasing dissolved drugs. It outlines some advantages of biodegradable polymers like sustained drug delivery and disadvantages like burst release. The document classifies polymers as biodegradable or non-biodegradable and describes factors that affect biodegradation rates. Examples of synthetic and natural biodegradable polymers are provided, such as polyglycolic acid, collagen, starch and chitosan.
The document discusses common problems encountered in tablet manufacturing including capping, lamination, cracking, chipping, sticking, picking, binding, and double impression. For each problem, the document defines it, identifies potential causes related to the formulation or manufacturing process/machine, and provides remedies. It also discusses defects that can occur during tablet coating like picking, sticking, twinning, color variation, orange peel, roughness, bridging, blistering, erosion, and peeling/frosting.
This document discusses rheology, which is the science describing the flow and deformation of matter under stress. It defines key terms like viscosity, shear stress, shear rate, and classifies fluids as Newtonian or non-Newtonian based on their relationship between shear stress and shear rate. Newtonian fluids have a constant viscosity regardless of shear rate, while non-Newtonian fluids have variable viscosity. Plastic, pseudoplastic, and dilatant behaviors are described for non-Newtonian fluids. Thixotropy, which is a time-dependent decrease and recovery of viscosity under shear, is also discussed. The document concludes by explaining the operation and calibration of common viscometers.
This document discusses various techniques to improve the solubility of poorly soluble drugs, which is important for developing effective dosage forms and achieving desired drug concentrations. It defines solubility and discusses the importance of solubility in drug development. Some key techniques covered are co-solvency, use of surfactants, solid dispersions, complexation, changing temperature, hydrotropy, polymorphism, amorphous forms, solvates, salt formation, and micronization/nanonization. The goal is to select the optimal method for a given drug to enhance dissolution and absorption.
This presentation discusses roller compactors, which are used to press powders into solid compacts like flakes or sheets. Key factors that affect roller compaction include compaction pressure, feeding screw speed, and roll speed. A roller compactor generally consists of a feeding system, compaction unit with counter-rotating rolls, and a size reduction unit. It works by applying force between the rolls to compact powders into a ribbon. Roller compactors can have either a fixed or floating gap between rolls. The major advantages include avoiding solvents, suitability for heat-sensitive compounds, and producing porous tablets for improved dissolution. Applications in pharmaceuticals include excipient production, drug compaction, herbal extract granulation, and
Tablets are one of the most common oral solid dosage forms. They can be produced through compression or molding methods. There are several types of tablets including compressed, sugar-coated, film-coated, enteric-coated, and controlled-release tablets. Tablets contain active drug ingredients along with excipients that serve various purposes like diluents, binders, lubricants, disintegrants, and colors. Excipients are carefully selected to provide tablets with properties like hardness, disintegration, and appropriate dissolution for drug release.
This document provides an overview of a seminar presentation on drug stability given by Ms. Swati S. Bharati to Mumbai University. The presentation covers topics such as the importance of stability testing, degradation pathways including physical, chemical and microbial degradation, kinetic stability, and solution and solid state stability. It defines stability and the purpose of stability studies. Examples are provided to illustrate different types of degradation pathways and how they can be prevented.
Direct compression is the most advanced technology. It involves only blending and compression. Thus offering advantage particularly in terms of speedy production. Because it requires fewer unit operations, less machinery, reduced number of personnel and considerably less processing time along with increased product stability.
Hot melt extrusion with PVA – solubility enhancement, supersaturation perform...MilliporeSigma
Hot melt extrusion has successfully emerged as an innovative manufacturing technology in pharmaceutical industry for the creation of amorphous solid dispersions (ASDs).
In this webinar you will learn about the potential of hot melt extrusion to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA) as a matrix polymer. We will provide an overview about different types of solid dispersions and their evolution in the pharmaceutical field. A brief introduction in hot melt extrusion processing will be given as well as actual formulation trends. You will get insights in potential down-stream options to create your final dosage form and you will gain ideas on how to speed up your formulation development.
A detailed background of PVA will be provided including its physical properties as well as its regulatory status. PVA is more than a polymer. Due to its amphiphilic structure it has the potential to improve the supersaturation of low soluble APIs and to prevent precipitation after release. This highlights the versatility of PVA as an advanced polymer for HME applications and we will guide you through our latest research activities so that you can leverage our knowledge to improve your formulations.
This webinar includes:
- The current status and further potential of HME in pharmaceutical industry
- Advantages of PVA in the field of ASDs: Solubility improvement, impact on supersaturation potential, stability data generated on sample formulations & downstream options
- Deep dive into latest research activities: Permeation studies with Caco-2 cell membranes, pH shift studies to investigate supersaturation potential, ongoing research activities to get to know a more detailed understanding of matrix systems and their intermolecular interactions
In this webinar, you will learn:
- which potential hot melt extrusion has, to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA)
- why PVA is more than just a polymer
- how to create your final dosage form and speed up your formulation development
Hot melt extrusion with PVA – solubility enhancement, supersaturation perform...Merck Life Sciences
Hot melt extrusion has successfully emerged as an innovative manufacturing technology in pharmaceutical industry for the creation of amorphous solid dispersions (ASDs).
In this webinar you will learn about the potential of hot melt extrusion to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA) as a matrix polymer. We will provide an overview about different types of solid dispersions and their evolution in the pharmaceutical field. A brief introduction in hot melt extrusion processing will be given as well as actual formulation trends. You will get insights in potential down-stream options to create your final dosage form and you will gain ideas on how to speed up your formulation development.
A detailed background of PVA will be provided including its physical properties as well as its regulatory status. PVA is more than a polymer. Due to its amphiphilic structure it has the potential to improve the supersaturation of low soluble APIs and to prevent precipitation after release. This highlights the versatility of PVA as an advanced polymer for HME applications and we will guide you through our latest research activities so that you can leverage our knowledge to improve your formulations.
This webinar includes:
- The current status and further potential of HME in pharmaceutical industry
- Advantages of PVA in the field of ASDs: Solubility improvement, impact on supersaturation potential, stability data generated on sample formulations & downstream options
- Deep dive into latest research activities: Permeation studies with Caco-2 cell membranes, pH shift studies to investigate supersaturation potential, ongoing research activities to get to know a more detailed understanding of matrix systems and their intermolecular interactions
In this webinar, you will learn:
- which potential hot melt extrusion has, to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA)
- why PVA is more than just a polymer
- how to create your final dosage form and speed up your formulation development
Overcoming Challenges in Ophthalmic Formulations through Polymer Selection – ...Merck Life Sciences
Ophthalmic drug formulations are growing in importance due to the increased prevalence of eye-related disorders such as diabetic retinopathy and macular degeneration. However, ocular drug delivery is challenging due to unique anatomical and physiological barriers.
The low ocular bioavailability (<10%) of conventional ophthalmic formulations is driving the need for novel approaches to improve the delivery of the desired concentration, at the site of action, at a controlled rate.
This whitepaper provides an overview of polymers that can be used in ophthalmic formulations and highlights the advantages offered using polyvinyl alcohol (PVA) through case studies.
Find more information about excipients for liquid formulations on our website: https://www.sigmaaldrich.com/products/pharma-and-biopharma-manufacturing/formulation/liquid-formulation
Enhancement of Solubility By Solid Dispersion- Presented By Mr.Ajinkya Nikam...Ajinkya Nikam
1) Solid dispersion is a method to improve the solubility of poorly water soluble drugs by dispersing drugs in a hydrophilic carrier. It involves mixing the drug with a carrier on a molecular or microscopic level.
2) Common methods for preparing solid dispersions include fusion, solvent evaporation, spray drying, and melt extrusion. These methods aim to convert crystalline drugs into amorphous forms within hydrophilic carriers.
3) Characterization techniques like DSC, XRD, and dissolution testing are used to analyze the molecular state of drugs in solid dispersions and evaluate increases in solubility and dissolution rate compared to raw drugs.
Technology Transfer From R and D to Pilot Plant to Plant for Non-Sterile Semi...shiv
Technology transfer is important for successful progress of drug development from research to commercialization. This presentation discusses technology transfer from research and development to pilot plant and full-scale production of non-sterile semisolids. It covers the importance of pilot plants in scale-up, factors to consider in scaling up semisolids like mixing equipment and homogenization processes. SUPAC guidelines for scale-up and post-approval changes are also summarized. A case study demonstrates issues encountered like congealing during scale-up of a cream formulation containing diethylene glycol monoethyl ether from lab to pilot scale.
formulation and evaluation of microbeadsgurleen kaur
Microencapsulation has been employed to sustain the drug release, reduce or eliminate drug related adverse effects, dose intake and improve the bioavailability inspite drug undergo extensive first pass metabolism ultimately improve the compliance in pharmacotherapy of inflammation and pain.
Microencapsulation by ionotropic gelation technique is one of the widely used method for preparation of calcium alginate beads which has ability to form gels reaction with calcium salts .
Microencapsulation has been employed to sustain the drug release, reduce or eliminate drug related adverse effects, dose intake and improve the bioavailability inspite drug undergo extensive first pass metabolism ultimately improve the compliance in pharmacotherapy of inflammation and pain.
Microencapsulation by ionotropic gelation technique is one of the widely used method for preparation of calcium alginate beads which has ability to form gels reaction with calcium salts .
Watch this webinar here: https://bit.ly/32cbiHt
This webinar will introduce PVA as an optimized excipient for sustained release formulations. Combining direct-compression compatibility with a robust and reliable matrix formation, PVA has the potential to enhance sustained release formulations.
By modifying the drug release characteristics, significant therapeutic benefits can be achieved, such as improved efficacy of the therapeutic agent, reduced adverse effects, optimization of the dosing scheme and overall improvement in patient compliance. There are numerous approaches for modified release, each with its own benefits and drawbacks. This webinar will present PVA, a fully-synthetic polymer, for optimized sustained release matrix formulations. Combining robust and reliable gel-forming behavior with optimized tableting properties, PVA provides solutions for the most challenging sustained release formulations.
In this webinar, you will learn:
• How the gel-formation properties of PVA introduce sustained release
• Why compatibility with direct compression leads to simplified formulations
• That PVA can provide flexibility in sustained release formulation development
PVA for sustained release: theory and practiceMilliporeSigma
The document discusses using polyvinyl alcohol (PVA) for sustained release drug delivery formulations. It begins with an introduction that outlines the benefits of modified oral drug release and some common sustained release approaches. The main challenges with sustained release formulations are identified as dose dumping, batch-to-batch consistency, process cost efficiency, API-dependent release kinetics, and flexible modification of release profiles. Parteck SRP 80, a synthetic PVA polymer, is presented as a solution that provides consistent performance across batches and reduces processing costs through direct compression. The document demonstrates how Parteck SRP 80 can achieve sustained release of various active pharmaceutical ingredients without dose dumping, even in the presence of alcohol. The release profile can also be flexibly modified
Stability_Considerations_In_Formulation_Development.pptRavi Kumar G
The document discusses the importance of stability considerations in pharmaceutical development. It states that stability is a key attribute and integral part of drug and dosage form development. The aim of pharmaceutical development is to design stable products and control factors preventing quality and stability issues. Stability evaluations start early in drug development and cover various stages. The physical state of drugs can influence stability, dissolution, and bioavailability. Factors like polymorphism, hydration, and processing need to be controlled. Excipient selection and manufacturing processes also impact stability and should be considered during formulation development.
This document discusses choosing antimicrobial preservatives for pharmaceutical products. It covers how pH, combinations of preservatives, and other factors influence preservative efficacy. Common preservatives like parabens, benzalkonium chloride, and phenols are discussed in terms of their antimicrobial spectrum and optimal pH ranges. The complexity of dermal products means microstasis rather than microcidality may be acceptable. Factors that can compromise preservative efficacy include interactions with other product components and chemical or physical instability over the product shelf life.
CO–PROCESSED EXCIPIENTS FOR TABLETS.pdfYamini Shah
Purpose of the present review is to provide an in depth knowledge on recent developments in excipients preparation, technology and approaches involved in their formation and development. Excipients play an important role in dosage form development. In conventional formulation of dosage forms, each excipient is used to provide its required function/performance. Presently, excipient manufacturers have focused their attention on producing a multifunctional excipients with improvement in their performance and quality of dosage form. Manipulation in the functionality of excipient is provided by the co-processing of two or more existing excipients.
New microsoft office power point presentationMayuri Yadav
This document provides an introduction and overview of nanosuspensions for pharmaceutical applications. It was prepared by Mayuri B. Yadav and guided by Prof. Dr. S. N. Dhole of Modern College of Pharmacy in Pune, India. The document defines nanosuspensions and discusses their advantages such as improved bioavailability. It also outlines various preparation methods including media milling, high pressure homogenization, and the use of emulsions or microemulsions as templates. Evaluation parameters for nanosuspensions and some currently marketed formulations are also mentioned. The applications and conclusion state that nanosuspensions can effectively deliver poorly soluble drugs.
Background: The main objective of present research work is to formulate the Carbamazepine Fast Dissoving tablets. Carbamazepine, an
antiepileptic, belongs to BCS Class-II and used to control some types of seizures in the treatment of epilepsy and Neuropathic Pain by
blocking use-dependent sodium channels. Methods: The Fast Dissoving tablets of Carbamazepine were prepared employing different
concentrations of Crospovidone and Croscarmellose sodium in different combinations as a Sperdisintegrants by Direct Compression technique
using 32
factorial design. The concentration of Crospovidone and Croscarmellose sodium was selected as independent variables, X1
and X2 respectively whereas, wetting time, Disintegration time, t
50% ,t90%were selected as dependent variables. Results and Discussion:
Totally nine formulations were designed and are evaluated for hardness, friability, thickness, Assay, Wetting time, Disintegration time, Invitro
drug release. From the Results concluded that all the formulation were found to be with in the Pharmacopoeial limits and the In-vitro
dissolution profiles of all formulations were fitted in to different Kinetic models, the statistical parameters like intercept (a), slope (b) &
regression coefficient (r) were calculated. Polynomial equations were developed for Wetting time, Disintegration time, t50%, t90%. Validity of
developed polynomial equations were verified by designing 2 check point formulations (C1
, C2
). According to SUPAC guidelines the
formulation (F5
) containing combination of 9.375% Crospovidone and 9.375% Croscarmellose, is the most similar formulation (similarity factor
f
2
=82.675, dissimilarity factor f1
= 2.049 & No significant difference, t= 0.041) to marketed product (TEGRETOL-100). Conclusion: The
selected formulation (F5
) follows First order, Higuchi’s kinetics, mechanism of drug release was found to be Non-Fickian Diffusion (n= 0.665).
KEYWORDS: Carbamazepine, 3
2Factorial Design, Crospovidone , croscarmellose Sodium, Wetting Time, Disintegration Time.
Metabolix - PHA Modifiers as Polymeric Plasticizers and Process AidsMetabolix, Inc.
This document discusses using polyhydroxyalkanoates (PHAs) as polymeric plasticizers and process aids for PVC. PHAs were found to have similar properties to conventional ethylene copolymer resin modifiers for PVC, including lower migration rates than primary plasticizers like DINP. PHAs are also inherently miscible in PVC, making them easier to process than synthetic modifiers. Additionally, PHAs are fully bio-based and food contact approved, allowing for higher bio-content and a broader range of applications compared to conventional plasticizers.
1. The document describes the design of a prodrug for Albendazole to reduce its side effects. It involves synthesizing 5,6-dibromo benzimidazole, which is expected to have less toxicity.
2. The synthesis was carried out using normal techniques and the compound was evaluated using melting point, TLC, chemical tests and solubility studies. It showed less solubility, indicating lower adverse reactions.
3. The aim is to overcome side effects of Albendazole through structural modification via a prodrug approach to reduce adverse drug reactions.
The document discusses aspects of product design for compounded pharmaceuticals. It outlines differences between industrial and pharmacy compounding in terms of development characteristics and regulatory environment. It emphasizes applying a quality by design approach to development through understanding a product's intended use and performance. A case study describes developing a ready-to-administer bupivacaine-sufentanil solution to improve post-operative analgesia safety.
This document summarizes a presentation on novel solid oral drug formulations. It discusses advances in controlled drug delivery including oros and matrix/reservoir systems. It also discusses bioavailability enhancement techniques for poorly soluble drugs such as nanocrystals and solid dispersions. Nanocrystals are defined as nanoparticles composed entirely of drug with improved dissolution and saturation solubility. Methods for preparing nanocrystals include milling, homogenization and precipitation. Solid dispersions involve dispersing a drug in a carrier to improve solubility and can be classified as eutectic mixtures, solid solutions, or amorphous precipitations.
Introduction,Drug- Excipient Compatibility Experimental Design ,Excipient role in drug destabilization,DRUG EXCIPIENT COMPATIBILTY IN PARENTERAL PRODUCTS.This topic are described.
The document discusses the challenges of scaling up manufacturing for nano-products from lab to commercial scale. Some key challenges include ensuring reproducibility despite changes in operating conditions, maintaining physical stability over long processing times, achieving sterility through appropriate sterilization methods, and addressing environmental safety concerns from airborne nanoparticles. The document also presents solutions such as implementing quality control, identifying critical process parameters, selecting sterilization techniques carefully, and containing nanoparticles in liquid environments. A case study on scaling up emulsion-based ibuprofen nanoparticles 20-fold found similar particle sizes but lower drug loading at larger scale. Overall, addressing scale-up issues is important for commercializing nanomedicines.
Similar to Conference on Co- micronization by PH.D. Jérôme Hecq (20)
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Nano-gold for Cancer Therapy chemistry investigatory projectSIVAVINAYAKPK
chemistry investigatory project
The development of nanogold-based cancer therapy could revolutionize oncology by providing a more targeted, less invasive treatment option. This project contributes to the growing body of research aimed at harnessing nanotechnology for medical applications, paving the way for future clinical trials and potential commercial applications.
Cancer remains one of the leading causes of death worldwide, prompting the need for innovative treatment methods. Nanotechnology offers promising new approaches, including the use of gold nanoparticles (nanogold) for targeted cancer therapy. Nanogold particles possess unique physical and chemical properties that make them suitable for drug delivery, imaging, and photothermal therapy.
Osvaldo Bernardo Muchanga-GASTROINTESTINAL INFECTIONS AND GASTRITIS-2024.pdfOsvaldo Bernardo Muchanga
GASTROINTESTINAL INFECTIONS AND GASTRITIS
Osvaldo Bernardo Muchanga
Gastrointestinal Infections
GASTROINTESTINAL INFECTIONS result from the ingestion of pathogens that cause infections at the level of this tract, generally being transmitted by food, water and hands contaminated by microorganisms such as E. coli, Salmonella, Shigella, Vibrio cholerae, Campylobacter, Staphylococcus, Rotavirus among others that are generally contained in feces, thus configuring a FECAL-ORAL type of transmission.
Among the factors that lead to the occurrence of gastrointestinal infections are the hygienic and sanitary deficiencies that characterize our markets and other places where raw or cooked food is sold, poor environmental sanitation in communities, deficiencies in water treatment (or in the process of its plumbing), risky hygienic-sanitary habits (not washing hands after major and/or minor needs), among others.
These are generally consequences (signs and symptoms) resulting from gastrointestinal infections: diarrhea, vomiting, fever and malaise, among others.
The treatment consists of replacing lost liquids and electrolytes (drinking drinking water and other recommended liquids, including consumption of juicy fruits such as papayas, apples, pears, among others that contain water in their composition).
To prevent this, it is necessary to promote health education, improve the hygienic-sanitary conditions of markets and communities in general as a way of promoting, preserving and prolonging PUBLIC HEALTH.
Gastritis and Gastric Health
Gastric Health is one of the most relevant concerns in human health, with gastrointestinal infections being among the main illnesses that affect humans.
Among gastric problems, we have GASTRITIS AND GASTRIC ULCERS as the main public health problems. Gastritis and gastric ulcers normally result from inflammation and corrosion of the walls of the stomach (gastric mucosa) and are generally associated (caused) by the bacterium Helicobacter pylor, which, according to the literature, this bacterium settles on these walls (of the stomach) and starts to release urease that ends up altering the normal pH of the stomach (acid), which leads to inflammation and corrosion of the mucous membranes and consequent gastritis or ulcers, respectively.
In addition to bacterial infections, gastritis and gastric ulcers are associated with several factors, with emphasis on prolonged fasting, chemical substances including drugs, alcohol, foods with strong seasonings including chilli, which ends up causing inflammation of the stomach walls and/or corrosion. of the same, resulting in the appearance of wounds and consequent gastritis or ulcers, respectively.
Among patients with gastritis and/or ulcers, one of the dilemmas is associated with the foods to consume in order to minimize the sensation of pain and discomfort.
Computer in pharmaceutical research and development-Mpharm(Pharmaceutics)MuskanShingari
Statistics- Statistics is the science of collecting, organizing, presenting, analyzing and interpreting numerical data to assist in making more effective decisions.
A statistics is a measure which is used to estimate the population parameter
Parameters-It is used to describe the properties of an entire population.
Examples-Measures of central tendency Dispersion, Variance, Standard Deviation (SD), Absolute Error, Mean Absolute Error (MAE), Eigen Value
STUDIES IN SUPPORT OF SPECIAL POPULATIONS: GERIATRICS E7shruti jagirdar
Unit 4: MRA 103T Regulatory affairs
This guideline is directed principally toward new Molecular Entities that are
likely to have significant use in the elderly, either because the disease intended
to be treated is characteristically a disease of aging ( e.g., Alzheimer's disease) or
because the population to be treated is known to include substantial numbers of
geriatric patients (e.g., hypertension).
Discover the benefits of homeopathic medicine for irregular periods with our guide on 5 common remedies. Learn how these natural treatments can help regulate menstrual cycles and improve overall menstrual health.
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The skin is the largest organ and its health plays a vital role among the other sense organs. The skin concerns like acne breakout, psoriasis, or anything similar along the lines, finding a qualified and experienced dermatologist becomes paramount.
5-hydroxytryptamine or 5-HT or Serotonin is a neurotransmitter that serves a range of roles in the human body. It is sometimes referred to as the happy chemical since it promotes overall well-being and happiness.
It is mostly found in the brain, intestines, and blood platelets.
5-HT is utilised to transport messages between nerve cells, is known to be involved in smooth muscle contraction, and adds to overall well-being and pleasure, among other benefits. 5-HT regulates the body's sleep-wake cycles and internal clock by acting as a precursor to melatonin.
It is hypothesised to regulate hunger, emotions, motor, cognitive, and autonomic processes.
Are you looking for a long-lasting solution to your missing tooth?
Dental implants are the most common type of method for replacing the missing tooth. Unlike dentures or bridges, implants are surgically placed in the jawbone. In layman’s terms, a dental implant is similar to the natural root of the tooth. It offers a stable foundation for the artificial tooth giving it the look, feel, and function similar to the natural tooth.
- Video recording of this lecture in English language: https://youtu.be/Pt1nA32sdHQ
- Video recording of this lecture in Arabic language: https://youtu.be/uFdc9F0rlP0
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
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How to Control Your Asthma Tips by gokuldas hospital.Gokuldas Hospital
Respiratory issues like asthma are the most sensitive issue that is affecting millions worldwide. It hampers the daily activities leaving the body tired and breathless.
The key to a good grip on asthma is proper knowledge and management strategies. Understanding the patient-specific symptoms and carving out an effective treatment likewise is the best way to keep asthma under control.
3. Référence
PrésentationGénérale-Confidentiel
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INTRODUCTION
Formulation strategies used to enhance solubility /
dissolution rate / oral bioavailability
Formulation strategy selection: Consider multiple variables
- API
- Excipients
- Drug load (vs. dose)
- Manufacturing process
Composition Performance
- Solubility
- Dissolution
- Bioavailability
- Food effect
- Chemical stability (compatibility)
- Physical stability
- Safety
4. Référence
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INTRODUCTION
Factors influencing solubility
Molecular structure (molecular weight / size, polarity / functional
groups)
Temperature
pKa and GIT pH profile
Surfactants
Solid state (crystalline state: polymorphs, pseudopolymorphs,
amorphous)
Particle size (influence: size<100nm - Ostwald)
Illustration of the calculated effect of particle diameter on Cs/C∞ for a particle having a
molecular weight of 708, a density of 1g/ml and an interfacial surface tension of 50 (blue),
75 (green) and 100 (red) dyn cm-1. (Kipp, 2004. Int. J. Pharm., 284 (1-2), 109-122)
5. Référence
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INTRODUCTION
Factors influencing dissolution
Noyes-Whitney
Parameter Definition Physicochemical characteristic in vivo factor
D Diffusion coefficient (solute) Molecular size of solute particle GIT fluids viscosity
A Specific surface area of dispersed particles Particle size Presence of surfactants
h Thickness of diffusion layer - GIT motility
S Saturation solubility of API Solid state, polarity,… pH, surfactants
Cb
Solute concentration in the dissolution media at
time t - GIT fluids volume
7. Référence
PrésentationGénérale-Confidentiel
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MICRONIZATION
Micronization
« Universal » formulation strategy applicable to most APIs
independently of their physicochemical properties:
− Molecular weight / size / structure
− Log P
− pKa
− Solubility in organic solvents or excipients
− Chemical stability (temperature, compatibility issues)
− Melting point: Low MP APIs may have a tendency to show agglomeration
during the micronization process (ball milling > jet milling) => cryomilling
No use of excipients, solvents
8. Référence
PrésentationGénérale-Confidentiel
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MICRONIZATION
Micronization vs. oral bioavailability
For drugs showing poor oral bioavailability due to low solubility
and not exclusively due to their poor dissolution behavior,
micronization may have a low or no impact on bioavailability
=> Nanomilling (PSD: 50-500nm)
=> Co-micronization with pharmaceutical excipients
allowing to increase solubility (i.e. surfactants, pH
modifying agents)
9. Référence
PrésentationGénérale-Confidentiel
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MICRONIZATION
Micronization vs. oral bioavailability
A micronized powder will generally be presenting particle surfaces
that are highly cohesive (VDW interactions, electrostatic
attraction) due to the high energy brought during the size
reduction process and that will lead to particle agglomeration and
subsequent problems:
>Poor flowability
>Low bulk density
>Increased poor wettability characteristics
>Reduced effective surface area with potential negative impact on drug
dissolution rate
=> Co-micronization of the drug with selected
pharmaceutical excipients allows to reduce these
inter-particular attractions and thus agglomeration
11. Référence
PrésentationGénérale-Confidentiel
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MICRONIZATION
Co-micronization vs. Micronization
Modification of surface properties of the drug particles
- Decrease of agglomeration phenomenon
Micronization Co-micronization
Spence et al., 2005. Pharm. Dev. Tech., 10, 451-460
Pfizer CI-1040 / MCC (90/10 w/w)Solubility < 1µg/ml
Log D: 3.55 (pH 7.4)
F(%) rats Micronized: 68.2
Co-micronized: 85.3
12. Référence
PrésentationGénérale-Confidentiel
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MICRONIZATION
Co-micronization vs. Micronization
Modification of surface properties of the drug particles
- Enhancement of hydrophilic character of micronized particle surface
(surfactant, water soluble excipients): Impact on wettability and
solubilization properties
Micronisation Co-micronisation Physical blend (µized API + exc)
14. Référence
PrésentationGénérale-Confidentiel
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MICRONIZATION
Co-micronization vs. Micronization
Promote specific interactions between the API and the selected
pharmaceutical excipient
- Amorphous form formation & stabilization
Maclean et al., 2011. J. Pharm. Sci., 100 (8), 3332-3344
Sulindac
Sulindac : Neusilin 1:1 w:w
→Stable > 4 months 40°C/75%RH
vs. immediate crystallization (24h at
25°C/60%RH) for amorphous sulindac (no
Neusilin) obtained by quench-cooling
→ Amorphous form of Sulindac stabilized through
interactions with Neusilin
15. Référence
PrésentationGénérale-Confidentiel
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MICRONIZATION
Co-micronization vs. Micronization
Promote specific interactions between the API and the selected
pharmaceutical excipient
- Amorphous form formation & stabilization
Maclean et al., 2011. J. Pharm. Sci., 100 (8), 3332-3344
Sulindac
Sulindac : Neusilin 1:1 w:w
Acidic drugs: reported interactions with Neusilin or other silicates:
Hydrogen bonding with silanol groups / rings
Ion Dipole-Dipole interactions with metal ions (Mg, Al)
⇒ Complex formation - salt formation?
www.neusilin.com
16. Référence
PrésentationGénérale-Confidentiel
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MICRONIZATION
Co-micronization vs. Micronization
Promote specific interactions between the API and the selected
pharmaceutical excipient
Gupta et al., 2003. J. Pharm. Sci., 92, 536-551
Ketoprofen : Neusilin 1:5 w:w
Decrease of the CO stretching peak at 1697cm-1 as function of
milling time
⇒ dissociation of the ketoprofen dimer
Amorphous state created during milling different than for the
melt-quenched amorphous ketoprofen
⇒ Preferred interaction (H bonding) with Neusilin
Hypothesis of salt formation (carboxylate formation)
Free acid carboxylic CO stretch
H-Bonding phenomenon with silicates reported for other acidic
drugs such as indomethacin and Naproxen but also for drugs not
having proton-donating groups (ex Progesterone)
17. Référence
PrésentationGénérale-Confidentiel
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MICRONIZATION
Co-micronization vs. Micronization
Promote specific interactions between the API and the selected
pharmaceutical excipient
- Solid dispersion preparation could also be achieved through co-
micronization using organic polymers such as Povidone (complete
amorphisation) and poloxamers (partial amorphisation)
Yang et al., 2012. Chem. Pharm. Bull., 60 (7), 837-845
Dipfluzine
Povidone
Dipfluzine
PVP
Dipfluzine:PVP 1:3 w:w physical blend
Dipfluzine:PVP 1:3 w:w co-grinding 30 min
Dipfluzine:PVP 1:3 w:w co-grinding 1 hour
Dipfluzine:PVP 1:3 w:w co-grinding 2 hours
Dipfluzine:PVP 1:3 w:w co-grinding 3 hours
⇒ Chemical shift of API CO stretch
18. Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Selection of the pharmaceutical excipient
Physicochemical properties of the excipient
>Melting point: Low melting point excipient may be an issue (material
agglomeration → product properties / process jamming)
− Difference between ball milling and jet milling: process/product temperature
Pluronic F68 (poloxamer): MP: 52°C
Pluronic F68 (bulk product) Pluronic F68 (Jet-mill) Pluronic F68 (Cryo Ball-mill)
Saleem and Smith, 2010. AAPS PharmSciTech,
11 (4) , 1642-1649
50µm 50µm
19. Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Selection of the pharmaceutical excipient
Physicochemical properties of the excipient
>Extent of particle size reduction dependent on the mechanical
properties of the material which determine the resistance to breaking
and the propagation of fracture
Mechanical properties (determined by nanoindentation):
− Hardness: determines the resistance of a material to plastic deformation
− Elasticity: determines the resistance of a material to elastic deformation.
Defined by Young’s modulus.
⇒ Hard and elastic material will require more energy for particle breakage
⇒ Process energy and time may be higher/longer during co-micronization
with soft materials in order to decrease API particle size (vs. micronization)
20. Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Selection of the pharmaceutical excipient
Physicochemical properties of the excipient
>Particle size distribution vs. API PSD
− blend homogeneity before co-micronization
>Density vs. API density
− homogeneity during co-micronization (when considering jet-milling /
particle acceleration (Venturi) – classification)
− Particles with higher porosity may break easier
24. Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Controls on produced samples
Particle size distribution analysis
>Diffraction laser, scanning electronic microscopy (+ morphology / API-excipient
association)
Specific surface area
> BET (Brunauer–Emmett–Teller)
Solid state (polymorphic/ crystalline modifications)
>X-ray diffraction, differential scanning calorimetry
API / excipient interactions
>Infra-Red (FTIR) spectroscopy, differential scanning calorimetry
25. Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Controls on produced samples
Blend uniformity (API)
>Before and after co-micronization
In vitro dissolution (SINK conditions) and dynamic solubility test
(non SINK conditions – evaluation of supersaturation/precipitation
phenomenon)
Pharmacokinetic study - oral bioavailability study (rodent/ non
rodent species)
27. Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Precellys®: Innovative technology and high performance
preformulation tool
High throughput ball milling technology developed and patented by
Bertin Technologies allowing to produce a specific 3D (precession)
movement of tubes and beads
Stainless steel or ceramic (stabilized zirconium oxyde) beads
28. Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Precellys®: Innovative technology and high performance
preformulation tool
4 available tube size: 0,5ml / 2ml / 7ml / 15ml
>Allowing to work on very small sample size (20mg - 1000mg)
Small milling time: 30 to 90 seconds cycles (hold time of 20 to 120
seconds between cycles)
High milling speed: 4500rpm – 10000rpm
Milling chamber temperature monitoring and control possible
(range 10-20°C) in order to limit product temperature increase
during the milling operation – patented cooling system (Cryolis®)
29. Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Micronization / co-micronization : available industrial
manufacturing equipment and process
Mechanical milling:
>Ball milling
− Stainless steel (316L), ceramic (ZrO2),…
− Particle size reduction by friction and attrition (bead/bead or bead/wall)
and little or no impact of particle/particle collision
− Non negligible risk of product contamination (bead/wall and abrasive API)
− Batch size (few grams – 100kg)
− Long milling process time (product temperature increase vs. API stability
and particle agglomeration for soft materials ><cryomilling)
− Process parameters influencing particle size distribution: bead type, bead
number, milling time, rotation/milling speed
30. Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Micronization / co-micronization : available industrial
manufacturing equipment and process
Air jet milling:
>Characteristics:
− Particle size reduction through particle/particle collisions (particle speed :
300-500m/s)
− Particle classification system as function of size
− Low risk of product contamination
− Batch size (10g – tons) – continuous manufacturing process
− Short milling process time (limited product temperature increase:
product temperature ∼ process gas temperature)
− Particle size distribution span: jet-mill < ball mill
31. Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Micronization / co-micronization : available industrial
manufacturing equipment and process
Air jet milling:
>Equipments:
− Spiral jet mill (fluid energy mill)
- Particle acceleration by Venturi effect
- Classification (size) par centrifugal force
- Process parameters influencing particle size distribution:
Feed size, Feeding pressure, Grinding pressure,
Feed rate (⇒ specific energy J/g)
⇒ Possibility to align the discharging point of 2 screw feeders
in the center of the Venturi feeding cone
http://www.sreenex.com/html/bulk_airjetmill.htm
32. Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Micronization / co-micronization : available industrial
manufacturing equipment and process
Air jet milling:
>Equipments:
− Fluidized-bed jet mill
- Particle acceleration by radial fluidized air jets
- Classification (size) par centrifugal force and dynamic rotors
- No limitations in feed size (vs spiral jet-mill: blockage of feed hopper)
www.hmicronpowder.com/products/product/alpine-
afg-fluidized-bed-jet-mill
39. Référence
PrésentationGénérale-Confidentiel
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CONCLUSION
Co-micronization: Formulation strategy defining innovative
API/excipient associations in order to enhance oral bioavailability of
poorly water soluble APIs
Impact on physical properties of API (particle surface modification ⇒ flowability,
agglomeration, wettability, dissolution) + creation of specific API/excipient
interactions
Allows to work in favorable API / excipient ratio (highly dosed APIs – final dosage
form development)
Easily accessible at industrial manufacturing scale using well established
manufacturing process
Precellys®: High performance innovative preformulation tool to
evaluate the potential benefits of co-micronization
Work on very low amount of API (NCE)
High throughput screening capabilities: test of diverse range of pharmaceutical
excipients in one single run
Results predictive of prototypes obtained using conventional micronization
equipments (ball milling, jet milling)