The document discusses hot melt extrusion for amorphous formulations. It summarizes that about 40% of new APIs have poor solubility and are classified as Class II or IV in the Biopharmaceutical Classification System. Hot melt extrusion is presented as a continuous process that can transform crystalline drugs into amorphous forms through melting and mixing with polymers without using solvents. The document reviews the processing, performance, stability, and analytical characterization of drug-polymer hot melt extrudates using solubility parameters, thermal analysis, rheology, dissolution testing, and other techniques. It finds that hot melt extrusion improves drug dissolution by creating amorphous solid dispersions and that performance depends on drug-polymer interactions and pH conditions.
High shear granulation is a shaping process for granulation that has been enhanced for application in the pharmaceutical industry. A binder liquid is fed to the powder particles in a closed container with blending tools and a chopper. Dense granules are formed through the liquid and solid bridges that result.
Caleva Process Solutions
http://www.caleva.com
Another resourceful Powerpoint Presentation from Caleva Process Solutions. These selection of slides will provide you with some very useful information on Extrusion Spheronization. This includes general information, the process of Extrusion Spheronization, Wet Massing and Pelletization!
For more information on Extrusion Spheronization, visit:
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High shear granulation is a shaping process for granulation that has been enhanced for application in the pharmaceutical industry. A binder liquid is fed to the powder particles in a closed container with blending tools and a chopper. Dense granules are formed through the liquid and solid bridges that result.
Caleva Process Solutions
http://www.caleva.com
Another resourceful Powerpoint Presentation from Caleva Process Solutions. These selection of slides will provide you with some very useful information on Extrusion Spheronization. This includes general information, the process of Extrusion Spheronization, Wet Massing and Pelletization!
For more information on Extrusion Spheronization, visit:
http://caleva.com/
WHAT IS COMPRESSION ?
Compression means reduction of bulk volume of material as a result of the removal of gaseous phase (air) by applied pressure
WHAT IS CONSOLIDATION?
Consolidation is an increase in mechanical strength of material resulting from particle - particle interactions.
A Primer on Hard Gelatin Capsule ManufacturingVivek Sinha
31/03/2015
Hard gelatin capsule shells are used as soluble containers for incorporation of drugs or nutritional
supplements, usually in the form of powders, pellets or granules in the healthcare industry. They are
commonly intended for oral administration having its advantages over other dosage forms that are
used widely by pharmaceutical companies to develop different medicaments and ensure stability of
the product throughout the shelf life. Since it serves as a major excipient for the manufacture of
pharmaceutical products, the quality attributes of hard capsule shells is very vital for performance
and stability of the final product.
Pharmaceutical products are categorized as high quality and high risk product administered to fight
various types of acute and chronic illnesses where the performance of the product should be
reproducible every time it is administered. The capsule shell consists of two cylindrical parts i.e. the
cap and body; both are open at one extreme. Other extreme of both is hemispherical; the open end
of cap overlaps the open end of body and maintains a closure with a typical lock system. Hence, it is
very important that the product achieves the label claim as set forth and is not contaminated and
readily available to the patients. Benchmarking of developments and manufacturing processes in the
pharmaceutical industry as against other industries led to the concept of Quality by Design or QbD.
Over the past few years, QbD has gained considerable acceptance throughout pharmaceutical
industry and has been successfully applied. The key quality attributes of capsules that determine the
process ability on the high speed filling machine are the dimensional characteristics and weight
variability.
The potential variations of empty hard capsules as an input material and its potential impact on
finished product quality has been studied and high consistency within the specification of the critical
quality parameters is confirmed. Annual product quality review needs to be performed using defined
sampling size against set of verification criteria. The built-in quality approach begins at the
development stage of new product where even factors impacting the performance of hard capsules
i.e. formulation, filling machine type, etc., is given due consideration. The selection of proper raw
material, the process validations and stability studies are to be conducted for suitability. The process
conditions should be maintained along with appropriate in-process quality checks. Final release of
product can be done by QA after product and document review. The data on process capability,
trends of quality parameters, technical specification and the evaluation procedure should be
maintained and submitted based on the current level of quality standards.
WHAT IS COMPRESSION ?
Compression means reduction of bulk volume of material as a result of the removal of gaseous phase (air) by applied pressure
WHAT IS CONSOLIDATION?
Consolidation is an increase in mechanical strength of material resulting from particle - particle interactions.
A Primer on Hard Gelatin Capsule ManufacturingVivek Sinha
31/03/2015
Hard gelatin capsule shells are used as soluble containers for incorporation of drugs or nutritional
supplements, usually in the form of powders, pellets or granules in the healthcare industry. They are
commonly intended for oral administration having its advantages over other dosage forms that are
used widely by pharmaceutical companies to develop different medicaments and ensure stability of
the product throughout the shelf life. Since it serves as a major excipient for the manufacture of
pharmaceutical products, the quality attributes of hard capsule shells is very vital for performance
and stability of the final product.
Pharmaceutical products are categorized as high quality and high risk product administered to fight
various types of acute and chronic illnesses where the performance of the product should be
reproducible every time it is administered. The capsule shell consists of two cylindrical parts i.e. the
cap and body; both are open at one extreme. Other extreme of both is hemispherical; the open end
of cap overlaps the open end of body and maintains a closure with a typical lock system. Hence, it is
very important that the product achieves the label claim as set forth and is not contaminated and
readily available to the patients. Benchmarking of developments and manufacturing processes in the
pharmaceutical industry as against other industries led to the concept of Quality by Design or QbD.
Over the past few years, QbD has gained considerable acceptance throughout pharmaceutical
industry and has been successfully applied. The key quality attributes of capsules that determine the
process ability on the high speed filling machine are the dimensional characteristics and weight
variability.
The potential variations of empty hard capsules as an input material and its potential impact on
finished product quality has been studied and high consistency within the specification of the critical
quality parameters is confirmed. Annual product quality review needs to be performed using defined
sampling size against set of verification criteria. The built-in quality approach begins at the
development stage of new product where even factors impacting the performance of hard capsules
i.e. formulation, filling machine type, etc., is given due consideration. The selection of proper raw
material, the process validations and stability studies are to be conducted for suitability. The process
conditions should be maintained along with appropriate in-process quality checks. Final release of
product can be done by QA after product and document review. The data on process capability,
trends of quality parameters, technical specification and the evaluation procedure should be
maintained and submitted based on the current level of quality standards.
We are one of the leading companies excelling in manufacturing construction equipment, storage tanks, mechanical valves and seals, and water tubes. These are known for high performance, durability and precision.
Extrusion processing using a combination of moisture, pressure, temperature and mechanical shear, is been used in the feed industry. It results in physical and chemical changes such as ingredient particle size reduction, starch gelatinization and inactivation of enzymes. Mild extrusion processing usually enhances the digestibility of plant proteins.
We specialize in the manufacturing and rebuilding of screws, barrels, removable mixers, tips, end caps, nozzles, and a large variety of other specialized machining components, including augers, tie bars, and rotors.
AAPS2011 Oral--Analytical Techniques To Characterize Excipient Stability &...mzhou45
AAPS2011 Oral Presentation at Hot Melt Extrusion Symposium on Oct. 26, 2011 in Washington DC Titled "Analytical Techniques to Characterize the Stability & Degradation of Polymeric Excipients from Hot Melt Extrusion Processing
Carbohydrates are an excellent source of energy and carbon in feed formulations. They can be easily distinguished from the other energy yielding nutrients in terms of their abundance and low price. To illustrate, the collective global production of the major cereal grains i.e., maize, wheat and rice amounted to a colossal 2.5 billion tonnes in the year 2013 (FAO). The total carbohydrate content and the digestible fraction of starch and sugars in these grains can be roughly estimated to be about 2.1 and 1.75 billion tonnes, respectively (www.feedipedia.org). Besides, the unit cost of carbohydrate sources is almost three to five fold less than that of the protein and lipid sources of interest. Therefore, the inclusion level of carbohydrates in commercial fish feed assumes direct economic significance i.e., in terms of lower feed cost per unit weight gain.
Particle Size Analysis for Pharmaceutical Homogenization Process DevelopmentHORIBA Particle
Guest speaker Dr. Daniel Huang of Novartis joins HORIBA Scientific (http://www.horiba.com/particle) to speak about homogenization process development.
High-pressure homogenization has been used to prepare emulsions in a broad range of industries. Particle size distribution and emulsion stability are two key properties of the system essential to a successful downstream application. In this study, Daniel and his colleagues have investigated the effects of process conditions on droplet size and coalescence rate of the emulsion systems.
Particle Size Determination and Raman Spectroscopic Evaluation of a Semi-soli...HORIBA Particle
Dr. Robert Lee of Particle Sciences joins HORIBA Scientific to discuss how his company uses the LA-950 particle size analyzer and XploRA raman spectrometer to characterize semi-solid dosage forms.
Stationary Phase and Mobile Phase Selection for Liquid Chromatography
The presentation focuses on how to choose the appropriate mode of separation, the correct column and highlights the importance of the correct mobile phase. This approach will be applied to a wide selection of compound types ranging from proteins, peptides, glycans to small pharmaceutical molecules and their metabolites. It will also look at specific application areas for monoclonal antibody analysis, namely: titer, aggregation, charge and oxidation variant. Platform methods for biologics characterization are also discussed.
Cell culture refers to the removal of cells from an animal or plant and their subsequent growth in a favorable artificial environment. The cells may be removed from the tissue directly and disaggregated by enzymatic or mechanical means before cultivation, or they may be derived from a cell line or cell strain that has already been established.
More cell culture techniques and best practices here. http://owl.li/dgS2Y
Similar to Hot Melt Extrusion For Amorphous Formulations (6)
3. Introduction
• Biopharmaceutical Classification System (BCS)
High Solubility Low Solubility
High permeability Class I Class II
Low permeability Class III Class IV
• High throughput screening is resulting in more complex API structures
with an increase in Class II and Class IV APIs.
• About 40 % of all new APIs fail in development due to their poor solubility.
• There is a trend for recent drug candidates to be in Class II.
4. Introduction
• Class II and Class IV APIs
• Crystalline Hydrophobic Compounds
Crystalline Amorphous
5. Introduction
• Process • Advantages
– API, Thermoplastic Polymers – Continuous Process
– Heating, Melting-Softening, Mixing – Absence of Solvents
– Extrusion (Cylinders, Films) – No Drying Step
– Amorphous Transformation
– Cooling (On the Conveyor)
– Solid Solutions
– Plasticizers, Surfactants, Antioxidants
– Interactions
11. Processing (Thermal Analysis) ITZ
• Disobeying of Gordan-Taylor equation could
be due to counter-ionic interaction between
IND and Eudragit EPO
IND
GSF
13. Processing (Rheological Evaluation)
Comparison of softening temperatures of PMs Comparison of η0 at same softening temperatures
IND (100 rpm), ITZ (150 rpm), and GSF (200 rpm) at their softening temperatures
14. Processing (Rheological Evaluation)
η0 was dependent on the concentration and state of the drug in the PMs at the softening temperatures
IND GSF
ITZ ITZ
18. Processing (Summary)
• Solubility Parameters
– Prediction of immiscibility between ITZ and Eudragit EPO
• Thermal Analysis
– Confirmation of immiscibility between ITZ and Eudragit EPO
– Prediction of physical state of the extrudates
– Exceptions to Gordon Taylor equation – stronger counter-ionic interactions (IND : Eudragit EPO)
• Rheological Evaluation
– Estimation of processing conditions for HME – softening temperatures and zero rate viscosity
• Hot Melt Extrusion
– Transparent glassy HMEs (Solid Solutions)
28. Performance (FT-IR Spectroscopy) (GSF)
• Intermolecular interactions between the
drugs and the polymers during HME
• Not possible to distinguish the stronger
counter-ionic interactions
32. Performance (Summary)
• PXRD Analysis
– Amorphous transformation due to HME
– Amorphous transformation – Independent of API concentration
• PLM
– No surface crystallization of APIs on the HMEs due to dissolution medium
– No reduction in dissolution due to surface crystallization
• FTIR Spectroscopy
– Intermolecular interactions between the drugs and the polymers during HME
– Not possible to distinguish the stronger counter-ionic interactions
• Dissolution Study
– Dissolution of all the drugs was improved using HME technology
– Improvement was dependent on pH dependent ionization and drug-polymer interactions for IND and ITZ than
merely amorphous transformation
– Improvement was dependent on both amorphous transformation and drug-polymer interactions for GSF
34. Stability (Methods)
• Hot Melt Extrusion • Moisture Analysis
– Leistritz Hot Melt Extruder Micro-18 Model, Four – Los on Drying (LOD), Pre-weighed Aluminium Pans,
Barrels, Conveying Elements, Co-Rotating Twin- % Weight Loss, % Moisture Content
Screws, 400g PM, 15g/min, Extrudates – Milled,
Screened, Stored in Desiccator at 5°C • Thermal Analysis
– 6-8 mg Sample, Heat-Cool-Heat Cycle, Heating Rate
• Stability Chambers 10°C/min, Cooling Rate 50ºC/min, Melting Point,
– Saturated Salt Solutions, Closed Porous Plastic Glass Transition Temperature
Containers, Analysis – 1, 3, 6, 9, 12 Weeks
• Powder X-Ray Diffraction (PXRD)
– Milled HMEs, Cu K α Radiation, Angular Range of 1
< 2θ < 40°, Step Width 0.02°, Scan Rate 1°/ per
minute
• Dissolution Study
– USP Dissolution Apparatus II, 0.1N HCl (SGF),
Phosphate Buffer pH 6.8 (SIF), 37°C, 50rpm
– IND (265nm), and ITZ (263nm)
35. Stability (Hot Melt Extrudates)
• Four barrel system of Leistritz extruder with
all the conveying elements of co-rotating
twin screws simulated well with the design
of Mini-Lab MicroCompounder
• Transparent glassy HMEs could be produced
using temperatures and speeds estimated in
part I
48. Stability (Dissolution Study – IND : Eudragit EPO)
Possible increase in counter-ionic interactions with the increase in temperature and humidity over time
49. Stability (Summary)
• Hot Melt Extrusion
– Possible to predict feasibility of HME production at large scale by simulating designs of the extruders
• Moisture Analysis
– Moisture content increased with time, temperature, and humidity
– The hygroscopicity of vinyl polymer was higher than that of methacrylic and cellulosic polymers
• Thermal Analysis
– Amorphous ITZ was physically unstable at higher temperatures and humidity levels
– The crystallization and phase separation of ITZ could be determined using DSC
• Powder X-Ray Diffraction
– Crystallization of ITZ could be confirmed
• Dissolution Study
– Dissolution of ITZ was reduced for stability samples with crystallization
– Dissolution of IND was reduced for stability samples with chemical degradation
– Supersaturation of ITZ and IND was improved over stability period for HMEs with polymers counter-ionic to these drugs
50. Exciting Discovery
• Drug-Polymer interactions play an important role in
– Processing HME product
– Improving dissolution rate
– Enhancing supersaturation levels
• The supersaturation of ionic drugs was improved in unfavorable pH conditions possibly due to
improvement in counter-ionic interactions with the polymers
• These counter-ionic interactions could have been increased due to water assisted charge transfer
• The controlled use of temperature and moisture could be beneficial to improve the intermolecular
interactions to sustain the supersaturation levels
51. Acknowledgements
• Dr. Hossein Zia
• Dr. Harpreet Sandhu
• Dr. Navnit Shah
• Dr. Waseem Malick
• Mr. Bharat Patel
• Committee Members
• Family and Friends