The document discusses dissolution testing requirements for artemisinin-based combination therapies (ACTs). It summarizes the availability of dissolution methods and criteria in pharmacopeial monographs, including the International Pharmacopoeia (PhInt) and United States Pharmacopeia (USP). The key points are:
- Dissolution testing is generally required for ACT solid oral dosage forms, as the artemisinin derivatives have low solubility.
- PhInt and USP monographs provide dissolution methods and criteria for some single-drug ACT products, but not fixed-dose combinations.
- Guidance is given on developing a discriminating dissolution method, including considering changes to formulation and manufacturing process.
- Compar
This document discusses stability studies for active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs). It covers topics like applicable guidelines, definitions, stability protocols and reports, stability testing of APIs and FPPs, evaluation of results, and conclusions. Key points include the types of batches tested in stability studies, parameters analyzed, acceptance criteria for significant changes, and guidelines for evaluating stability study results to determine a retest period or shelf life.
This document outlines an agenda for a training workshop on pharmaceutical development with a focus on paediatric formulations being held from October 15-19, 2007 in Tallinn, Estonia. The workshop will cover various topics including pre-formulation analytical studies, stress testing APIs, the impact of impurities on API specifications, excipient compatibility studies, degradation pathways, and the role of API processing in product instability. The goal is to discuss how preformulation studies influence key decisions in API and drug product development and support establishing appropriate container closure systems and analytical methods.
Dissolution testing measures the percentage of active pharmaceutical ingredient (API) released from solid oral dosage forms like tablets and capsules over time under controlled conditions. It is important for developing formulations, setting specifications, comparing batch quality, and evaluating post-approval changes. The test involves measuring API dissolved in different media like pH 1.2, 4.5 and 6.8 buffers using validated analytical methods. Dissolution profiles are compared using f2 calculations or by ensuring 85% dissolution within 15 minutes to determine similarity. Comparative dissolution data should be reported with purpose, conditions, results and conclusion.
1) The document provides guidance on in vitro and in vivo evaluation of drug products, including characterization of the drug substance and product through physicochemical properties and dissolution testing.
2) It outlines the types of pharmacokinetic and pharmacodynamic studies that should be conducted to understand how the drug substance and product properties relate to clinical performance.
3) The document emphasizes that in vivo studies are generally needed to demonstrate bioequivalence, but in some cases in vitro studies may suffice, such as for BCS Class I drugs with rapid dissolution.
This document outlines an agenda for a training workshop on pharmaceutical development with a focus on paediatric formulations being held from October 15-19, 2007 in Tallinn, Estonia. The workshop will cover various topics including pre-formulation analytical studies, stress testing APIs, the impact of impurities on API specifications, excipient compatibility studies, degradation pathways like hydrolysis and oxidation, and the role of preformulation in selecting appropriate drug products and manufacturing processes. One of the presentations will focus on pre-formulation analytical studies and their impact on API and formulation development.
This document describes the formulation, optimization, and evaluation of liquisolid tablets containing tadalafil to improve its bioavailability. Tadalafil was selected as a model drug due to its low water solubility. Several liquisolid formulations were prepared containing different ratios of carrier to coating materials in the powder substrate and a fixed liquid medication. The dissolution profiles of the liquisolid tablets were determined and compared to a commercial product. Prepared liquisolid tablets showed enhanced dissolution profiles compared to the commercial product, indicating improved bioavailability. The optimized formulation exhibited consistent performance over stability testing. Overall, the liquisolid technique improved the dissolution and predicted bioavailability of tadalafil tablets.
This document provides guidelines for conducting bioequivalence studies in ASEAN countries. It adopts guidelines from the European Medicines Agency with some adaptations for ASEAN applications. The guidelines specify the requirements for the design, conduct, and evaluation of bioequivalence studies for immediate release dosage forms. It addresses study designs, subjects, conduct, characteristics to be investigated, strengths to be studied, bioanalytical methodology, evaluation, and special considerations for narrow therapeutic index or highly variable drugs. It also provides guidance on in vitro dissolution testing and requirements for bioequivalence study reports.
This document discusses stability studies for active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs). It covers topics like applicable guidelines, definitions, stability protocols and reports, stability testing of APIs and FPPs, evaluation of results, and conclusions. Key points include the types of batches tested in stability studies, parameters analyzed, acceptance criteria for significant changes, and guidelines for evaluating stability study results to determine a retest period or shelf life.
This document outlines an agenda for a training workshop on pharmaceutical development with a focus on paediatric formulations being held from October 15-19, 2007 in Tallinn, Estonia. The workshop will cover various topics including pre-formulation analytical studies, stress testing APIs, the impact of impurities on API specifications, excipient compatibility studies, degradation pathways, and the role of API processing in product instability. The goal is to discuss how preformulation studies influence key decisions in API and drug product development and support establishing appropriate container closure systems and analytical methods.
Dissolution testing measures the percentage of active pharmaceutical ingredient (API) released from solid oral dosage forms like tablets and capsules over time under controlled conditions. It is important for developing formulations, setting specifications, comparing batch quality, and evaluating post-approval changes. The test involves measuring API dissolved in different media like pH 1.2, 4.5 and 6.8 buffers using validated analytical methods. Dissolution profiles are compared using f2 calculations or by ensuring 85% dissolution within 15 minutes to determine similarity. Comparative dissolution data should be reported with purpose, conditions, results and conclusion.
1) The document provides guidance on in vitro and in vivo evaluation of drug products, including characterization of the drug substance and product through physicochemical properties and dissolution testing.
2) It outlines the types of pharmacokinetic and pharmacodynamic studies that should be conducted to understand how the drug substance and product properties relate to clinical performance.
3) The document emphasizes that in vivo studies are generally needed to demonstrate bioequivalence, but in some cases in vitro studies may suffice, such as for BCS Class I drugs with rapid dissolution.
This document outlines an agenda for a training workshop on pharmaceutical development with a focus on paediatric formulations being held from October 15-19, 2007 in Tallinn, Estonia. The workshop will cover various topics including pre-formulation analytical studies, stress testing APIs, the impact of impurities on API specifications, excipient compatibility studies, degradation pathways like hydrolysis and oxidation, and the role of preformulation in selecting appropriate drug products and manufacturing processes. One of the presentations will focus on pre-formulation analytical studies and their impact on API and formulation development.
This document describes the formulation, optimization, and evaluation of liquisolid tablets containing tadalafil to improve its bioavailability. Tadalafil was selected as a model drug due to its low water solubility. Several liquisolid formulations were prepared containing different ratios of carrier to coating materials in the powder substrate and a fixed liquid medication. The dissolution profiles of the liquisolid tablets were determined and compared to a commercial product. Prepared liquisolid tablets showed enhanced dissolution profiles compared to the commercial product, indicating improved bioavailability. The optimized formulation exhibited consistent performance over stability testing. Overall, the liquisolid technique improved the dissolution and predicted bioavailability of tadalafil tablets.
This document provides guidelines for conducting bioequivalence studies in ASEAN countries. It adopts guidelines from the European Medicines Agency with some adaptations for ASEAN applications. The guidelines specify the requirements for the design, conduct, and evaluation of bioequivalence studies for immediate release dosage forms. It addresses study designs, subjects, conduct, characteristics to be investigated, strengths to be studied, bioanalytical methodology, evaluation, and special considerations for narrow therapeutic index or highly variable drugs. It also provides guidance on in vitro dissolution testing and requirements for bioequivalence study reports.
The document discusses planning and reporting of stability studies for pharmaceutical products. It provides definitions of key terms from ICH guidelines related to stability testing of active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs). Specifically, it defines terms like re-test date, shelf life, formal stability studies, stress testing, primary and commitment batches, and more. It also discusses requirements for stability protocols and reports, including details of batches tested, storage conditions, analytical methods used, and results. Forced degradation studies aim to identify potential degradation pathways and validate stability-indicating methods.
stability The ability of a pharmaceutical product to retain its chemical, physical, microbiological and biopharmaceutical properties within specified limits throughout its shelf-life.Why is stability of a drug important?
Drug stability affects the safety and efficacy of the drug product; degradation impurities may cause a loss of efficacy and generate possible adverse effects. Therefore, achieving the chemical and physical stability of drugs is essential to ensure their quality and safety.Common factors that affect this stability include temperature, light, pH, oxidation and enzymatic degradation. Special considerations are also required when dealing with chiral molecules, deuterated internal standards and large biomolecules.
The role of dissolution in the demonstration of bioequivalenceinemet
PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com
Abstract is available at http://www.pharmaconnectme.com
This document summarizes the presentation of a new RP-HPLC method for the simultaneous determination of metformin and evogliptin in bulk and pharmaceutical dosage forms. The method utilizes a Waters XTerra RP-18 column with a mobile phase of acetonitrile, potassium dihydrogen phosphate, and methanol. Metformin and evogliptin were well separated with retention times of 2.73 and 4.47 minutes, respectively. The method was validated per ICH guidelines and showed good linearity, accuracy, precision, specificity, robustness and sensitivity. Forced degradation studies indicated the method can separate metformin and evogliptin peaks in the presence of degradation products.
Bioequivalence biowaiver and ivivc studies 2014 newAsra Hameed
The document discusses bioequivalence and biopharmaceutics classification system. It defines bioequivalence as the absence of a significant difference in the rate and extent to which the active ingredient becomes available at the site of drug action when administered at the same molar dose under similar conditions. It also defines pharmaceutical equivalents and alternatives. The document discusses approaches to determine bioequivalence including in vivo and in vitro methods. It provides details on bioequivalence study design, components, and considerations. Finally, it introduces the biopharmaceutics classification system and criteria for classifying drugs as highly soluble and highly permeable.
Bioavailability and bioequivalence – problems and pitfallsinemet
PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com
Abstract is available at http://www.pharmaconnectme.com
In this presentation I have mentioned whatever the possible relevant content/guidelines require for biowaiver application.
Citation Is done at the end of slide.
Content is up to date & true to my belief.
Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- anurag.dmk05@gmail.com
Comparison Of Two Marketed Nifedipine Modified Release[1]guest3309f3
This clinical study compared the pharmacokinetic properties of two 30 mg nifedipine modified-release tablet formulations when administered after a high-fat meal. Twelve healthy male volunteers participated in the randomized, open-label, two-period crossover study. In vitro dissolution experiments showed that one formulation had pH-dependent drug release while the other was pH-independent. After administration with food, significant differences were observed in the rate and extent of drug absorption between the formulations. The test formulation resulted in higher plasma concentrations and exposure compared to the reference formulation. Both treatments were well tolerated.
Dissolution Test development in regard to bioequivalenceanezlin
The document discusses the development and use of dissolution tests in assessing bioequivalence. It describes the Biopharmaceutics Classification System which categorizes drugs based on their solubility and permeability properties. Dissolution tests are used to evaluate product quality, ensure batch-to-batch consistency, and demonstrate similarity between formulations to support biowaivers. The key factors that influence dissolution testing are discussed, including test conditions, similarity calculations, and criteria for determining equivalent dissolution profiles. Montelukast sodium, a drug with low solubility, is presented as a case study.
Forced degradation studies for drug substances and drug products a regulator...Veeprho Laboratories
Introduction –
Various regulatory guidance are available which provides useful definitions and general comments about degradation studies. However, guidance concerning the scope, timing, degradation condition and best practices for degradation studies is very general. Various issues related to stress testing are addressed in numerous guidance documents but not always in the context of stress testing. Therefore, stress-testing conditions should be realistic and not excessive.
The forced degradation studies are also expected -
1. Structure elucidation of possible degradation path-ways.
2. Identification of degradation products that may be spontaneously generated during drug storage and during use.
3. To facilitate improvements in the manufacturing process and formulations in parallel with accelerated pharmaceutical stability studies.
The document discusses regulatory guidelines regarding polymorphs and cocrystals. It begins by defining polymorphs as crystalline, amorphous, solvate, and hydrate forms of a drug substance that have different molecular arrangements. It then discusses how polymorphism can impact properties like solubility, dissolution, bioavailability, and stability. The document also summarizes the "Ritonavir Story" which demonstrated these issues and prompted regulatory guidelines. It outlines the FDA guidance for assessing polymorphism in ANDAs, including decision trees for drug substances and products. Finally, it defines cocrystals and the characterization needed to demonstrate they are pharmaceutical cocrystals rather than salts.
This document provides guidance on photostability testing for new drug substances and products. It recommends a systematic approach to testing involving: 1) Tests on the drug substance; 2) Tests on the exposed drug product outside of packaging; 3) Tests on the product in immediate packaging, if needed; and 4) Tests in the marketing packaging, if needed. It describes appropriate light sources for testing and procedures for exposing samples alongside a chemical actinometer to ensure the specified light exposure. Testing continues through various levels of packaging until acceptable change is observed or a redesign is needed.
Dissolution Enhancement of BCS Class 4 Dssrugs Using Quality by Design Approa...inventionjournals
Solid dispersion is one of the vastly accepted and practically economical processes in bioavailability enhancement study. The present investigation deals mostly with increase in solubility and dissolution rate of BCS class 4 drugs for enhancement of oral bioavailability. For the same solid dispersion were prepared and analyzed for appropriate concentration of drug polymer ratio by phase solubility analysis. The solvent evaporation study widely accepted due to its efficient solid dispersion in lesser efforts. The study designs were prepared with specific concentration of drug and polymer ratio with the help of high throughput model i.e. Central Composite Design (by Design Expert trial copy) by specific design of experiment with full factorial design (DOE). The fixed variables were concentration of polymers and dependant variables were dissolution and permeability across bio-membrane in in-vitro model. The prepared dispersion investigated for dissolution and permeability improvement using USP Type II apparatus and modified everted gut sac model which leads to improvement of quality of whole formulation with Quality by design efficiently.
BCS Guideline for solubility and Dissolution.pptxImdad H. Mukeri
Briefly explanation of The Biopharmaceutics Classification System (BCS) of drug substance
and its solubility in the pH range of 1–7.5, absorption or intestinal membrane permeability
1.preformulation concept in Modern pharmaceutics.pptxPNMallikarjun
Preformulation is defined as the investigation of physical and chemical properties of a drug substance alone and when combined with excipients. The goal is to generate information to help formulators develop stable and safe dosage forms with good bioavailability. Some key tests include determining the drug's solubility, stability, and compatibility with various excipients using techniques like DSC, TLC, and HPLC. This provides critical data to guide the rational selection of dosage form and formulation components.
Bioavailability and bioequivalence studyMcpl Moshi
BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability.
It is a drug development tool that allows estimation of solubility, dissolution and intestinal permeability affect that oral drug absorption.
Kashikar V S
PES Modern College of Pharmacy ( for ladies), Moshi Pune
Bioavailability and Bioequivalence studyMcpl Moshi
Bioavailability and Bioequivalence study, BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability.
It is a drug development tool that allows estimation of solubility, dissolution and intestinal permeability affect that oral drug absorption.
The document describes the formulation and evaluation of ibuprofen suspension using natural and synthetic suspending agents. Four ibuprofen suspensions were prepared using different combinations of methylcellulose, fenugreek seed powder, and other excipients. The suspensions were evaluated for sedimentation volume, particle size, viscosity, pH, drug content, and in-vitro drug release. The F4 formulation containing both fenugreek seed powder and methylcellulose showed the best stability profile compared to the other formulations in the various evaluation tests.
DESIGN AND EVALUATION OF PULSATILE DRUG DELIVERY SYSTEM CONTAINING PANTOPRAZO...Reshma Fathima .K
The document describes the design and evaluation of a pulsatile drug delivery system containing pantoprazole sodium to mimic the circadian rhythm of peptic ulcer. Six formulations of core tablets were developed using different concentrations of superdisintegrants. Tablets were then coated with Eudragit S100 to achieve a lag time of 5 hours before drug release. Evaluation showed the core tablets had acceptable hardness, friability, weight variation and drug content. No chemical interactions between the drug and polymers were observed. When coated tablets were tested, dissolution was prevented for 5 hours followed by rapid and complete drug release, indicating the system could deliver the drug during morning hours to match peptic ulcer symptoms.
The document provides an overview of a course on fundamentals of electrochemistry. It includes the lecture topics, instructors, evaluation criteria, and concepts that will be covered over the course such as thermodynamics, electrode kinetics, voltammetric methods, and industrial applications. The course will involve assignments and a final exam. Key concepts that will be discussed include electrochemical potentials, activity, the Nernst equation, and examples of galvanic and electrolytic cells.
Hazard Analysis Critical Control Point (HACCP) is a food safety system used by food businesses to identify and control potential biological, chemical, and physical hazards. It involves identifying critical control points during food production where hazards could be prevented, eliminated, or reduced to safe levels. Businesses must establish critical limits for each control point, monitor the control points, and have corrective actions and record keeping procedures in place. Implementing HACCP helps businesses comply with food safety laws and prevent consumers from being exposed to health risks from food hazards.
The document discusses planning and reporting of stability studies for pharmaceutical products. It provides definitions of key terms from ICH guidelines related to stability testing of active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs). Specifically, it defines terms like re-test date, shelf life, formal stability studies, stress testing, primary and commitment batches, and more. It also discusses requirements for stability protocols and reports, including details of batches tested, storage conditions, analytical methods used, and results. Forced degradation studies aim to identify potential degradation pathways and validate stability-indicating methods.
stability The ability of a pharmaceutical product to retain its chemical, physical, microbiological and biopharmaceutical properties within specified limits throughout its shelf-life.Why is stability of a drug important?
Drug stability affects the safety and efficacy of the drug product; degradation impurities may cause a loss of efficacy and generate possible adverse effects. Therefore, achieving the chemical and physical stability of drugs is essential to ensure their quality and safety.Common factors that affect this stability include temperature, light, pH, oxidation and enzymatic degradation. Special considerations are also required when dealing with chiral molecules, deuterated internal standards and large biomolecules.
The role of dissolution in the demonstration of bioequivalenceinemet
PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com
Abstract is available at http://www.pharmaconnectme.com
This document summarizes the presentation of a new RP-HPLC method for the simultaneous determination of metformin and evogliptin in bulk and pharmaceutical dosage forms. The method utilizes a Waters XTerra RP-18 column with a mobile phase of acetonitrile, potassium dihydrogen phosphate, and methanol. Metformin and evogliptin were well separated with retention times of 2.73 and 4.47 minutes, respectively. The method was validated per ICH guidelines and showed good linearity, accuracy, precision, specificity, robustness and sensitivity. Forced degradation studies indicated the method can separate metformin and evogliptin peaks in the presence of degradation products.
Bioequivalence biowaiver and ivivc studies 2014 newAsra Hameed
The document discusses bioequivalence and biopharmaceutics classification system. It defines bioequivalence as the absence of a significant difference in the rate and extent to which the active ingredient becomes available at the site of drug action when administered at the same molar dose under similar conditions. It also defines pharmaceutical equivalents and alternatives. The document discusses approaches to determine bioequivalence including in vivo and in vitro methods. It provides details on bioequivalence study design, components, and considerations. Finally, it introduces the biopharmaceutics classification system and criteria for classifying drugs as highly soluble and highly permeable.
Bioavailability and bioequivalence – problems and pitfallsinemet
PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com
Abstract is available at http://www.pharmaconnectme.com
In this presentation I have mentioned whatever the possible relevant content/guidelines require for biowaiver application.
Citation Is done at the end of slide.
Content is up to date & true to my belief.
Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- anurag.dmk05@gmail.com
Comparison Of Two Marketed Nifedipine Modified Release[1]guest3309f3
This clinical study compared the pharmacokinetic properties of two 30 mg nifedipine modified-release tablet formulations when administered after a high-fat meal. Twelve healthy male volunteers participated in the randomized, open-label, two-period crossover study. In vitro dissolution experiments showed that one formulation had pH-dependent drug release while the other was pH-independent. After administration with food, significant differences were observed in the rate and extent of drug absorption between the formulations. The test formulation resulted in higher plasma concentrations and exposure compared to the reference formulation. Both treatments were well tolerated.
Dissolution Test development in regard to bioequivalenceanezlin
The document discusses the development and use of dissolution tests in assessing bioequivalence. It describes the Biopharmaceutics Classification System which categorizes drugs based on their solubility and permeability properties. Dissolution tests are used to evaluate product quality, ensure batch-to-batch consistency, and demonstrate similarity between formulations to support biowaivers. The key factors that influence dissolution testing are discussed, including test conditions, similarity calculations, and criteria for determining equivalent dissolution profiles. Montelukast sodium, a drug with low solubility, is presented as a case study.
Forced degradation studies for drug substances and drug products a regulator...Veeprho Laboratories
Introduction –
Various regulatory guidance are available which provides useful definitions and general comments about degradation studies. However, guidance concerning the scope, timing, degradation condition and best practices for degradation studies is very general. Various issues related to stress testing are addressed in numerous guidance documents but not always in the context of stress testing. Therefore, stress-testing conditions should be realistic and not excessive.
The forced degradation studies are also expected -
1. Structure elucidation of possible degradation path-ways.
2. Identification of degradation products that may be spontaneously generated during drug storage and during use.
3. To facilitate improvements in the manufacturing process and formulations in parallel with accelerated pharmaceutical stability studies.
The document discusses regulatory guidelines regarding polymorphs and cocrystals. It begins by defining polymorphs as crystalline, amorphous, solvate, and hydrate forms of a drug substance that have different molecular arrangements. It then discusses how polymorphism can impact properties like solubility, dissolution, bioavailability, and stability. The document also summarizes the "Ritonavir Story" which demonstrated these issues and prompted regulatory guidelines. It outlines the FDA guidance for assessing polymorphism in ANDAs, including decision trees for drug substances and products. Finally, it defines cocrystals and the characterization needed to demonstrate they are pharmaceutical cocrystals rather than salts.
This document provides guidance on photostability testing for new drug substances and products. It recommends a systematic approach to testing involving: 1) Tests on the drug substance; 2) Tests on the exposed drug product outside of packaging; 3) Tests on the product in immediate packaging, if needed; and 4) Tests in the marketing packaging, if needed. It describes appropriate light sources for testing and procedures for exposing samples alongside a chemical actinometer to ensure the specified light exposure. Testing continues through various levels of packaging until acceptable change is observed or a redesign is needed.
Dissolution Enhancement of BCS Class 4 Dssrugs Using Quality by Design Approa...inventionjournals
Solid dispersion is one of the vastly accepted and practically economical processes in bioavailability enhancement study. The present investigation deals mostly with increase in solubility and dissolution rate of BCS class 4 drugs for enhancement of oral bioavailability. For the same solid dispersion were prepared and analyzed for appropriate concentration of drug polymer ratio by phase solubility analysis. The solvent evaporation study widely accepted due to its efficient solid dispersion in lesser efforts. The study designs were prepared with specific concentration of drug and polymer ratio with the help of high throughput model i.e. Central Composite Design (by Design Expert trial copy) by specific design of experiment with full factorial design (DOE). The fixed variables were concentration of polymers and dependant variables were dissolution and permeability across bio-membrane in in-vitro model. The prepared dispersion investigated for dissolution and permeability improvement using USP Type II apparatus and modified everted gut sac model which leads to improvement of quality of whole formulation with Quality by design efficiently.
BCS Guideline for solubility and Dissolution.pptxImdad H. Mukeri
Briefly explanation of The Biopharmaceutics Classification System (BCS) of drug substance
and its solubility in the pH range of 1–7.5, absorption or intestinal membrane permeability
1.preformulation concept in Modern pharmaceutics.pptxPNMallikarjun
Preformulation is defined as the investigation of physical and chemical properties of a drug substance alone and when combined with excipients. The goal is to generate information to help formulators develop stable and safe dosage forms with good bioavailability. Some key tests include determining the drug's solubility, stability, and compatibility with various excipients using techniques like DSC, TLC, and HPLC. This provides critical data to guide the rational selection of dosage form and formulation components.
Bioavailability and bioequivalence studyMcpl Moshi
BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability.
It is a drug development tool that allows estimation of solubility, dissolution and intestinal permeability affect that oral drug absorption.
Kashikar V S
PES Modern College of Pharmacy ( for ladies), Moshi Pune
Bioavailability and Bioequivalence studyMcpl Moshi
Bioavailability and Bioequivalence study, BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability.
It is a drug development tool that allows estimation of solubility, dissolution and intestinal permeability affect that oral drug absorption.
The document describes the formulation and evaluation of ibuprofen suspension using natural and synthetic suspending agents. Four ibuprofen suspensions were prepared using different combinations of methylcellulose, fenugreek seed powder, and other excipients. The suspensions were evaluated for sedimentation volume, particle size, viscosity, pH, drug content, and in-vitro drug release. The F4 formulation containing both fenugreek seed powder and methylcellulose showed the best stability profile compared to the other formulations in the various evaluation tests.
DESIGN AND EVALUATION OF PULSATILE DRUG DELIVERY SYSTEM CONTAINING PANTOPRAZO...Reshma Fathima .K
The document describes the design and evaluation of a pulsatile drug delivery system containing pantoprazole sodium to mimic the circadian rhythm of peptic ulcer. Six formulations of core tablets were developed using different concentrations of superdisintegrants. Tablets were then coated with Eudragit S100 to achieve a lag time of 5 hours before drug release. Evaluation showed the core tablets had acceptable hardness, friability, weight variation and drug content. No chemical interactions between the drug and polymers were observed. When coated tablets were tested, dissolution was prevented for 5 hours followed by rapid and complete drug release, indicating the system could deliver the drug during morning hours to match peptic ulcer symptoms.
The document provides an overview of a course on fundamentals of electrochemistry. It includes the lecture topics, instructors, evaluation criteria, and concepts that will be covered over the course such as thermodynamics, electrode kinetics, voltammetric methods, and industrial applications. The course will involve assignments and a final exam. Key concepts that will be discussed include electrochemical potentials, activity, the Nernst equation, and examples of galvanic and electrolytic cells.
Hazard Analysis Critical Control Point (HACCP) is a food safety system used by food businesses to identify and control potential biological, chemical, and physical hazards. It involves identifying critical control points during food production where hazards could be prevented, eliminated, or reduced to safe levels. Businesses must establish critical limits for each control point, monitor the control points, and have corrective actions and record keeping procedures in place. Implementing HACCP helps businesses comply with food safety laws and prevent consumers from being exposed to health risks from food hazards.
Alexander Fleming accidentally discovered penicillin in 1928 when he observed bacteria-free zones around mold colonies growing in petri dishes. Penicillin was the first natural antibiotic compound and works by inhibiting bacterial cell wall synthesis. Since then, over 100 different antibiotics have been discovered that work through various mechanisms like inhibiting protein synthesis or nucleic acid replication. However, antibiotic resistance has become a major problem requiring prudent antibiotic use and new antibiotic development.
Bacterial plasmids are small, circular pieces of DNA that are separate from the bacterial chromosome. Plasmids commonly contain genes that provide useful traits to bacteria like antibiotic resistance, but are not essential for survival. Plasmids can be transferred between bacteria through conjugation. There are different types of plasmids classified by their functions, such as fertility plasmids involved in conjugation, resistance plasmids containing antibiotic resistance genes, and virulence plasmids that can make bacteria pathogenic. Plasmids are useful in genetic engineering and cloning because they can be easily manipulated in the laboratory by inserting foreign DNA fragments using restriction enzymes and ligase. This allows bacteria to produce proteins like human insulin.
This document discusses the use of bacteria for genetic engineering and biotechnology. Bacteria are well-suited for this purpose because they are easy and inexpensive to grow, can grow quickly, and are easily manipulated in the laboratory. Their DNA can be easily inserted and isolated. Bacteria also contain natural plasmids and viruses that can act as vectors to insert recombinant DNA. Plasmids are small, circular pieces of DNA that are not essential but can contain useful genes. They allow genetic material to be exchanged between bacteria and can be manipulated in the laboratory to insert foreign DNA and propagate those genes. This allows bacteria to be transformed by taking in new DNA, such as human genes, and produce useful proteins like insulin.
The document provides an overview of Lean Six Sigma as a process improvement methodology. It discusses key Lean concepts like eliminating waste, standardizing processes, and continuous improvement. It also explains Six Sigma's statistical focus on reducing defects and variation. The DMAIC process of Define, Measure, Analyze, Improve, Control is introduced as the framework for process optimization projects using this methodology.
This document provides tips and guidelines for preparing and delivering an effective oral presentation at a conference. It discusses principles like talking instead of reading, standing up, making eye contact, and practicing. Specific tips include expecting nerves, preparing thoroughly, focusing on the audience, using examples, simplifying technical details, and having a clear structure with an outline, background, methods, results and summary. The document also covers designing clear slides with a logical layout, appropriate fonts, colors and graphs. It emphasizes rehearsing and handling questions professionally.
About this webinar: This talk will introduce what cancer rehabilitation is, where it fits into the cancer trajectory, and who can benefit from it. In addition, the current landscape of cancer rehabilitation in Canada will be discussed and the need for advocacy to increase access to this essential component of cancer care.
LGBTQ+ Adults: Unique Opportunities and Inclusive Approaches to CareVITASAuthor
This webinar helps clinicians understand the unique healthcare needs of the LGBTQ+ community, primarily in relation to end-of-life care. Topics include social and cultural background and challenges, healthcare disparities, advanced care planning, and strategies for reaching the community and improving quality of care.
Let's Talk About It: Breast Cancer (What is Mindset and Does it Really Matter?)bkling
Your mindset is the way you make sense of the world around you. This lens influences the way you think, the way you feel, and how you might behave in certain situations. Let's talk about mindset myths that can get us into trouble and ways to cultivate a mindset to support your cancer survivorship in authentic ways. Let’s Talk About It!
Feeding plate for a newborn with Cleft Palate.pptxSatvikaPrasad
A feeding plate is a prosthetic device used for newborns with a cleft palate to assist in feeding and improve nutrition intake. From a prosthodontic perspective, this plate acts as a barrier between the oral and nasal cavities, facilitating effective sucking and swallowing by providing a more normal anatomical structure. It helps to prevent milk from entering the nasal passage, thereby reducing the risk of aspiration and enhancing the infant's ability to feed efficiently. The feeding plate also aids in the development of the oral muscles and can contribute to better growth and weight gain. Its custom fabrication and proper fitting by a prosthodontist are crucial for ensuring comfort and functionality, as well as for minimizing potential complications. Early intervention with a feeding plate can significantly improve the quality of life for both the infant and the parents.
Stem Cell Solutions: Dr. David Greene's Path to Non-Surgical Cardiac CareDr. David Greene Arizona
Explore the groundbreaking work of Dr. David Greene, a pioneer in regenerative medicine, who is revolutionizing the field of cardiology through stem cell therapy in Arizona. This ppt delves into how Dr. Greene's innovative approach is providing non-surgical, effective treatments for heart disease, using the body's own cells to repair heart damage and improve patient outcomes. Learn about the science behind stem cell therapy, its benefits over traditional cardiac surgeries, and the promising future it holds for modern medicine. Join us as we uncover how Dr. Greene's commitment to stem cell research and therapy is setting new standards in healthcare and offering new hope to cardiac patients.
Letter to MREC - application to conduct studyAzreen Aj
Application to conduct study on research title 'Awareness and knowledge of oral cancer and precancer among dental outpatient in Klinik Pergigian Merlimau, Melaka'
Unlocking the Secrets to Safe Patient Handling.pdfLift Ability
Furthermore, the time constraints and workload in healthcare settings can make it challenging for caregivers to prioritise safe patient handling Australia practices, leading to shortcuts and increased risks.
Under Pressure : Kenneth Kruk's StrategyKenneth Kruk
Kenneth Kruk's story of transforming challenges into opportunities by leading successful medical record transitions and bridging scientific knowledge gaps during COVID-19.
KEY Points of Leicester travel clinic In London doc.docxNX Healthcare
In order to protect visitors' safety and wellbeing, Travel Clinic Leicester offers a wide range of travel-related health treatments, including individualized counseling and vaccines. Our team of medical experts specializes in getting people ready for international travel, with a particular emphasis on vaccines and health consultations to prevent travel-related illnesses. We provide a range of travel-related services, such as health concerns unique to a trip, prevention of malaria, and travel-related medical supplies. Our clinic is dedicated to providing top-notch care, keeping abreast of the most recent recommendations for vaccinations and travel health precautions. The goal of Travel Clinic Leicester is to keep you safe and well-rested no matter what kind of travel you choose—business, pleasure, or adventure.
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Anxiety, Trauma and Stressor Related Disorder.pptx
3-1_Dissolution WHO - Copy.ppt
1. Dissolution
Lynda Paleshnuik
Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and
assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.
2. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
2 |
Overview
Starting Point: Establishing Dissolution Criteria
– ACT Monograph Availability in the International Pharmacopeia
– Availability of other Pharmacopeial Monographs
Disintegration vs Dissolution
Prequalification Dissolution Requirements
Development Strategy for Dissolution Methods
Validation of Dissolution Methods
3. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
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Dissolution - Introduction
The pharmaceutical scientist would like to find a relationship
between an in vitro characteristic of a dosage form, and its in vivo
performance.
Disintegration was originally thought to be this characteristic. The
USP introduced its disintegration test in 1950.
With advances in methodology, the disintegration test was found to
be too insensitive, and dissolution test methods were introduced in
the USP in 1968.
Dissolution is principally useful as a QC test. It can be predictive of
in vivo behaviour, but this must be demonstrated by an in-vivo in-
vitro correlation study (IVIVC).
4. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
4 |
Dissolution - Introduction
USP <1088>:
“No product, including suspensions and chewable tablets, should
be developed without dissolution or drug release characterization
where a solid phase exists.”
and
“Dissolution testing is required for all solid oral Pharmacopeial
dosage forms in which absorption of the drug is necessary for the
product to exert the desired therapeutic effect. Exceptions are for
tablets meeting a requirement for completeness of solution or for
rapid (10 to 15 minutes) disintegration for soluble or radiolabeled
drugs.”
5. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
5 |
Establishing Dissolution Criteria
Starting point:
What monographs are available?
What are the dissolution requirements in the available
monographs?
What other sources of information are available?
6. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
6 |
Finding Current PhInt Monographs
The International Pharmacopeia Supplement 1 to the 4th
Edition (2008) is available at:
http://www.who.int/phint/en/p/docf/
For the latest monographs, including a list of those under
development:
https://www.who.int/medicines/publications/pharmacopoei
a/mono_dev/en/index.html
7. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
7 |
PhInt Monographs and Requirements:
ACT’s
ACT’s include 7 API’s present in 4 possible combinations.
PhInt monographs are available for all API’s and for the
following FPP’s:
Single-API FPP’s
Artemether capsules
Artemether tablets
Artesunate tablets
8. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
8 |
PhInt Monographs and Requirements
ACT’s (multiple API FPPs):
Artemether/lumefantrine tablets (new)
Artemether/lumefantrine oral suspension (new)
Note that the above are available under monograph
development (second link on previous slide), not in the
online PhInt (first link on previous slide).
9. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
9 |
PhInt Monographs
Monographs under development and future monographs:
Monographs in progress:
Amodiaquine tablets
Sulfadoxine/Pyrimethamine tablets.
Proposed for work:
Mefloquine tablets
10. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
10 |
PhInt Dissolution Requirements
Artemether capsules - Dissolution. Carry out the test as described
under 5.5 Dissolution test for solid oral dosage forms.
Artemether tablets – as above
Artesunate tablets – as above
Artemether/lumefantrine tablets – no reference to dissolution
Artemether/lumefantrine oral suspension – no reference to
dissolution, including in the referenced general monograph:
“Liquid preparations for oral use” under the section, “Powders for
oral solutions/suspensions/drops”
11. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
11 |
Availability in Other Pharmacopeia
BP 2008: no monographs.
USP 2009:
API’s: amodiaquine, amodiaquine HCl, mefloquine
Dosage Forms:
• Amodiaquine HCl Tablets
• Sulfadoxine/Pyrimethamine Tablets
For both of the above, dissolution limits are included.
12. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
12 |
USP Monograph
Dissolution Methods/Limits
Amodiaquine HCl Tablets
• Medium: water; 900 mL.
• Apparatus 2: 50 rpm.
• NLT 75% (Q) in 30 minutes
Sulfadoxine/Pyrimethamine Tablets
• Medium: pH 6.8 phosphate buffer, prepared as directed under Buffer
Solutions in the section Reagents, Indicators, and Solutions; 1000 mL.
• Apparatus 2: 75 rpm.
• NLT 60% (Q) each API in 30 minutes.
(The above are in USP 2009 and USP 2009 S1)
13. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
13 |
USP vs PhInt Dissolution for Solid Orals
The apparatus 1 (basket) and apparatus 2 (paddle) are
essentially the same in USP, BP and PhInt
pharmacopeia. (See next slides.)
The acceptance criteria in the PhInt dissolution chapter
for solid orals is the same as USP Acceptance Table 1, ie
S1/S2/S3 stages and reference to Q.
17. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
17 |
Disintegration (DT) Testing
For immediate release tablets and capsules, dissolution
rate is determined by:
1) Rate of release of the API from the matrix, and
2) The rate at which the API dissolves in the medium.
For highly soluble API’s, the rate is largely determined by
the disintegration of the dosage form.
18. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
18 |
Disintegration (DT) Testing
Note that disintegration is generally an in-process test
when the API is not highly soluble.
Disintegration is indicated in the PhInt General Chapter
on tablets for various tablet types (uncoated, soluble
tablets, effervescent tablets, coated tablets). However: a
statement is included regarding all tablets: “Where a
requirement for the “Dissolution test” is specified in
the individual monograph, the 5.3 Disintegration test
for tablets and capsules is not required”.
19. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
19 |
Disintegration vs Dissolution
ICH Q6: Disintegration may be substituted for dissolution when:
-rapidly dissolving FPP’s (dissolution >80% in 15 minutes at pH 1.2, 4.0 and
6.8) and FPP’s containing API’s which are highly soluble throughout the
physiological range (dose/solubility volume < 250 mL from pH 1.2 to 6.8)
Most appropriate when:
- relationship between DT and dissolution is established, or
- DT shown to be more discriminating than dissolution.
In these cases development information should be provided to support the
robustness of the formulation and manufacturing process with respect to the
selection of dissolution vs. disintegration testing (see Decision Tree #7(1)).
20. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
20 |
ICH Q6 Decision Tree 7/1
21. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
21 |
Disintegration vs Dissolution
In the introduction to the current PhInt, it states that
disintegration testing has been added to monographs for
tablets and capsules containing highly soluble API’s, for
example chloroquine sulfate tablets and isoniazid tablets.
“…the disintegration test is considered to be generally
satisfactory for such products”.
Note that API’s in ACT’s are generally low solubility,
and dissolution testing is required.
22. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
22 |
Prequalification Requirements
A discriminating dissolution method should be
developed for the final composition of the FPP, when
applicable. This is a general requirement for solid orals.
Limits should be set for each API in fixed-dose FPPs.
The dissolution method should be incorporated into the
stability and quality control programs (release and shelf-
life specifications). Release limits = Shelf-life limits.
Multipoint dissolution profiles of both the test and the
reference FPPs should be compared.
23. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
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Prequalification Requirements
A tabulated summary of the compositions of the FPP
batches (batch number, batch size, manufacturing date
and certificate of analysis at batch release) used in
clinical trials and in bioequivalence studies and a
presentation of dissolution profiles must be provided.
A discussion of the documented information and data
should be presented. Results from comparative in vitro
studies (e.g., dissolution) or comparative in vivo studies
(e.g., bioequivalence) should be discussed when
appropriate.
24. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
24 |
Supplement 1 to the Main Generics Guide:
Dissolution Testing
Suggested media for comparative dissolution studies:
pH 6.8 buffer
pH 4.5 buffer
pH 1.2 buffer or 0.1N HCl
Water may be used as an additional medium, especially
when the API is unstable in buffered media to the extent
that data is unusable.
25. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
25 |
Supplement 1 – Comparative Dissolution
Calculation of similarity:
If both test and reference products show >85%
dissolution in 15 minutes, profiles are considered similar
and f2 calculation is unnecessary.
Otherwise, calculate f2 (calculation next page). If f2>50,
the profiles are considered similar.
26. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
26 |
Supplement 1 – Comparative Dissolution
f2 is the similarity factor, n is the number of time points, R(t) is the
mean %drug dissolved (reference product), and T(t) is the mean
%drug dissolved (test product).
The evaluation of similarity is based on the conditions of:
A minimum of three time points (zero excluded); time points for
comparator and test products should be the same.
12 dosage units of each formulation;
27. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
27 |
Supplement 1 – Comparative Dissolution
A maximum of one time point after 85% of the comparator
product has been reached. If 85% is not reached due to
poor solubility, dissolution should be conducted until an
asymptote (plateau) is reached.
The RSD (relative standard deviation) of the mean of any
product should be <20% for the early time point and
<10% for subsequent time points.
28. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
28 |
Supplement 1 – Comparative Dissolution
Reporting data: the report should include at least:
1) Purpose of study
2) Products / batches information
• Batch numbers, manufacturing/expiry date, and packaging of the two
batches used in the study
• Batch manufacturing record(s), batch size(s), manufacturing sites and
CoAs for the batch(es) of the test product(s).
Note that the batches tested must be the batches of test
and comparator product used in the BE study.
29. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
29 |
Supplement 1 – Comparative Dissolution
3) Full dissolution conditions and method, as well as the
number of units (tablets, capsules, etc) per study. It
should be indicated how and when the samples were
filtered. Any problems with pH related stability of
samples should be indicated and discussed in terms
of preventative handling measures, analysis and
interpretation of data.
30. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
30 |
Supplement 1 – Comparative Dissolution
4) Analytical method (validated) or reference to part of
dossier
5) Results (% API dissolved)
• Tabulated (individual results, mean and %CV)
• Graphically
• Similarity determination / f2 calculation if necessary
6) Conclusion/recommendation
31. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
31 |
Development of a Discriminating Method
A method must be developed which is both
a) discriminating, and
b) rugged and reproducible enough for day-to-day
operation, and capable of transfer between labs.
The acceptance criteria should be representative of
multiple batches with the same formulation/manufacturing
process, including key batches (eg BE).
32. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
32 |
Development of a Discriminating Method
The method should be discriminating enough:
The procedure should be capable of distinguishing
significant changes in composition or manufacturing
process that might be expected to affect in vivo
performance.
The method should not be overly sensitive:
Assessing the results from multiple batches that
represent typical variability in composition and
manufacturing parameters may assist this evaluation.
33. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
33 |
Development of a Discriminating Method
Factors to consider:
Qualitative and quantitative excipient changes
Manufacturing parameters:
– Lubrication
– Blend time
– Compression force
– Drying parameters
34. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
34 |
Development Strategy for Dissolution
Methods
Adopt the compendial method if one exists
- exception: unsuitable (example interference)
When no compendial method exists:
- develop a method using compendial methodology (general
chapters) and a study of three factors.
35. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
35 |
Development Strategy
Documented dissolution study focuses on three factors:
1: -the physicochemical characteristics of the product
(solubility, pH and quantitation of API released)
2: -the extent and rate of release of API from the FPP
3: - QC of the system (performance checks)
36. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
36 |
Physicochemical characteristics
Solubility
pH
API quantitation
37. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
37 |
Physicochemical characteristics
Solubility:
Solubility of the API in 37◦C in water, other media (ie HCl)
or buffers of different pH should meet “sink condition”
(volume of medium at least three times that required in
order to form a saturated solution of API).
In the absence of sink conditions, investigate methods to
enhance solubility, eg use of a surfactant. If a surfactant
is used, its concentration should be properly justified (e.g.
typically <2% Sodium Lauryl Sulfate (SLS)).
38. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
38 |
Physicochemical characteristics
pH: water may be used as medium, however the effect of
the formulation on the pH of water must be investigated
and if it changes, the use of buffers or HCl should be
considered.
pH should have in-vivo relevance if possible;
Stability and solubility of API should be considered, for
example some ACT’s are unstable in acidic medium
39. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
39 |
Physicochemical characteristics
API quantitation:
UV is often used; for UV the applicant should have demonstrated:
a) non-interference with formulation components (spectra of API in
the formula and in standard solutions should be identical in
shape/magnitude);
b) linearity (absorbance vs concentration) up to the highest expected
concentration.
Note that these will be determined as part of routine validation.
Chromatography is often necessary instead of UV when there is
excipient interference, it is low dose or it is a FDC-FPP that
requires more sensitivity and/or selectivity.
40. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
40 |
Performance Checks
Performance checks include calibration of the system “with suitable
calibrators” (PhInt). The USP calibrator tablets are considered
acceptable for dissolution method calibration.
System suitability testing (SST) is required to be included in
methodology. For a dissolution method, limits should be
established for:
- Precision (≤ 2%) plus either:
- Peak asymmetry/tailing factor (preferable) (≤ 2) or
- Theoretical plates (≥ 2000) or
- Resolution (>2)
41. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
41 |
Development Strategy
Establish dissolution profiles in at least two media within
the physiological pH range. One should be a compendial
medium, if a monograph exists.
Investigation of more than one medium, or a single buffer
with different pH values or ionic strength, can aid in
determining the optimum medium for use in quality
control (eg to evaluate lot-to-lot changes).
42. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
42 |
Development Strategy
If no compendial monograph exists, a suitable procedure
should be developed based on the physicochemical
properties of both the API and the FPP.
Choosing a medium in which dissolution is relatively
slower, for eg pH close to the pKa value of the drug, may
be advantageous as it may be more discriminating.
Once a satisfactory system is achieved, the factors in its
development should be summarized so the assessor
can follow the evolution and determine whether the
system is appropriate.
43. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
43 |
Method Description
The written procedure should include:
Apparatus
Standard and sample preparation
Method of analysis (eg UV, HPLC)
Sampling procedure (intervals, filtration*, handling of samples,
dilutions)
Calculations
Acceptance Criteria
44. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
44 |
Method Description
Filtration:
It should be indicated how and when samples are filtered.
An inert filter is required with a suitable pore size. The
intent is to avoid a) adsorption of active from solution or
b) interference due to substances extractable by the
dissolution medium.
45. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
45 |
Sample Stability
Stability of samples:
Any problems with pH related stability of samples should
be indicated and discussed in terms of preventative
handling measures, analysis and interpretation of data.
Note that some of the ACT molecules are unstable in
acidic medium.
46. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
46 |
Appropriateness of Method
Check:
1) Whether BCS Class 1 or 3
2) Results (BE batch characteristics, COA’s, stability data)
3) Has data been provided to demonstrate the method is
discriminatory?
4) Published methods
47. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
47 |
BCS Classification
PhInt monographs for class 1 or 3 API’s have (or will
have) a standard dissolution method:
Paddle, 75 rpm
500 mL pH 6.8 phosphate buffer
Criteria: NLT 80% l.c. in 30 minutes
or
DT NMT 10 min
48. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
48 |
Justification Based on Results
ICHQ6 states that actual results obtained (batch analysis,
stability studies) should form the primary basis of all
justification.
Do results indicate the method is discriminating? (Results
of studies on different formulations
(qualitative/quantitative excipient differences), API particle
size distribution (PSD), process parameters or In-Process
Controls (eg hardness, coating thickness)).
49. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
49 |
Justification Based on Results
Example 1: FDC product with fairly rapid release of
both API’s;
> 80% dissolution is reached at 20 minutes (for both
APIs in product)
The next time point can be chosen, ie NLT 80% in 30
minutes. This would be considered an acceptable limit.
50. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
50 |
Justification Based on Results
Example 2: for slow dissolution of immediate release tablets, it
is recommended that two points be used.
The following behaviour is observed for a product:
Time (min): 10 20 30 45 60 90 120
% released: 15 33 49 68 83 98 102
Applicant proposed: ≥ 75 % (Q) in 120 minutes
Limits requested: (1) Limit should be tightened to Q = 75% in 90
minutes. (2) A limit should also be established at 45 minutes and
implemented immediately during stability studies.
51. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
51 |
Published Methods
Compendial general chapters
- PhInt: Methods of Analysis: 5.5 Dissolution test for solid
oral dosage forms.
- USP <711> Dissolution and <724> Drug Release
- USP <1088> In-Vitro and In-Vivo Evaluation of Dosage
Forms
- USP <1092> The Dissolution Procedure: Development
and Evaluation
52. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
52 |
Published Methods
2) FDA dissolution site
http://www.accessdata.fda.gov/scripts/cder/dissolution/
- Gives reference to USP monograph if one exists
- Gives approved method parameters where no monograph
exists.
53. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
53 |
Published Methods
For the 7 API’s in the ACT’s, the only hit on the FDA site
is for mefloquine HCl tablets:
Apparatus: Basket
Speed: 100 rpm
Medium: 900 mL SGF without enzyme
Sampling: 10, 20, 30, 45, and 60 minutes
54. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
54 |
ICH Q6 Decision Tree 7/2.
55. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
55 |
Validation
Validation:
Testing a method to demonstrate it is suitable for its
intended purpose and the results obtained are
meaningful.
Provides confidence that the method will perform properly
under intended conditions.
56. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
56 |
Validation
Compendial dissolution methods should be revalidated
(verified) for:
– Specificity
– Accuracy
– Precision (repeatability).
57. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
57 |
Validation
House dissolution methods (HPLC, UV) should be fully validated:
Specificity
Linearity
Accuracy
Repeatability
Intermediate precision
Robustness (performed but not provided)
58. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
58 |
Validation
Specificity: Chromatograms: sample containing placebo
excipients vs sample without these components.
Linearity: range to be validated: ±20% of limits; eg if
limits cover from 20% to 90% l.c. (controlled release),
linearity should cover 0-110% of l.c.
Coefficient of Determination (r2) ≥ 0.997
Accuracy: assay samples/placeboes spiked with API;
analysis in triplicate. A bias of 2% or less is acceptable.
59. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
59 |
Validation
Precision:
System precision
Repeatability (method precision)
Intermediate precision (precision with variations, eg days,
analysts, equipment)
Reproducibility (inter-laboratory trial)
60. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
60 |
Validation
Repeatability determination:
9 determinations covering the range, eg 3 concentrations
in triplicate (n=3)
OR
2 or 3 determinations on each of 3 days
OR
6 determinations at 100% of the concentration
62. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
62 |
Example Issues
Example 1:
Granules are formulated to be dispersed in water prior to
administration. The API is very bitter and granules are
coated to mask the taste.
The dissolution studies provided should include a
demonstration that the coating serves its purpose, ie it
can withstand the dispersion process. (Failure would
result in a product which cannot be taken due to
bitterness.)
63. Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
63 |
Example Issues
Example 2
For some FDC’s, the comparator is in the form of more
than one tablet. When running comparative dissolution,
only one tablet should be placed in any one vessel.
Therefore the evaluation may have to be performed one
API at a time.
If the study uses more than one tablet per vessel,
solubility issues arise.