Preformulation involves characterizing the physicochemical properties of a drug prior to formulation development. Key aspects of preformulation studied include determining solubility, stability, and bulk properties of the drug substance. Analytical methods are also developed to quantitatively analyze the drug. This information guides the selection of appropriate excipients and dosage forms that will deliver the drug safely and effectively.
Bio pharmaceutical classification System [BCS]Sagar Savale
The Biopharmaceutical Classification System was first developed by in 1995, by Amidon et al & his colleagues.
Definition:
“The Biopharmaceutical Classification System is a scientific framework for classifying a drug substance based on its aqueous solubility & intestinal permeability & dissolution rate”.
To saved time fast screening is required so drug substances are classified on basis of solubility and permeability. This classification is called Biopharmaceutical Classification System
This document discusses various techniques for enhancing drug solubility. It begins with an introduction to factors affecting drug solubility and processes of solubilization. Then it describes techniques such as co-solvency, use of surfactants, complexation, and solid state manipulation. Co-solvency uses water-miscible solvents to improve drug solubility. Surfactants form micelles above the critical micelle concentration that can solubilize drugs. Complexation with cyclodextrin can enhance aqueous solubility. Manipulating a drug's solid state, such as forming polymorphs, can also increase solubility. The document provides examples and mechanisms for each solubility enhancement technique.
This document discusses key concepts in preformulation testing. It begins by defining preformulation as investigating the physical and chemical properties of a drug substance alone and combined with excipients. The overall goal is to generate information useful for developing stable and safe dosage forms.
It then outlines some of the main steps in preformation process including assessing organoleptic properties, purity, particle size, melting point, stability, excipient compatibility, solubility, polymorphism, pH and salt formation. Specific tests are mentioned for many of these areas.
The document emphasizes that preformulation is important for aiding drug candidate selection, product design, decreasing time to market, and ensuring overall safety and efficacy of the final product
The three main rate limiting steps in drug absorption from oral solid dosage forms are disintegration, dissolution, and gastric emptying. Disintegration involves the breakdown of the solid dosage form into smaller particles so that the drug can be released. Dissolution is the process by which the drug becomes dissolved in water to be absorbed. Gastric emptying determines how quickly the drug formulation moves from the stomach into the intestines, where most absorption occurs. Several drug and formulation properties can impact these steps and influence overall drug absorption.
The document discusses the pH partition theory of drug absorption from the gastrointestinal tract. The theory states that a drug's absorption is governed by its dissociation constant (pKa), the lipid solubility of its unionized form, and the pH of the absorption site. According to the theory, only the unionized form of an acid or base drug can be absorbed if it is sufficiently lipid soluble. The fraction of a drug in its unionized form depends on the drug's pKa and the pH of the solution based on the Henderson-Hasselbalch equation. While the pH partition theory explains many observations, it has limitations such as not accounting for the presence of an unstirred water layer and virtual membrane pH at the absorption
This presentation summarizes various dissolution testing apparatus. It describes 7 types of apparatus recognized by USP, IP, BP and EP. The first four apparatus are commonly used and include the rotating basket, paddle, reciprocating cylinder and flow through cell. The presentation provides details on the design, working, and typical uses of each apparatus type. It also discusses commonly used dissolution media and concludes that the goal of dissolution testing is to ensure pharmaceutical quality and understand biopharmaceutical properties like rate and extent of drug absorption.
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.
Bio pharmaceutical classification System [BCS]Sagar Savale
The Biopharmaceutical Classification System was first developed by in 1995, by Amidon et al & his colleagues.
Definition:
“The Biopharmaceutical Classification System is a scientific framework for classifying a drug substance based on its aqueous solubility & intestinal permeability & dissolution rate”.
To saved time fast screening is required so drug substances are classified on basis of solubility and permeability. This classification is called Biopharmaceutical Classification System
This document discusses various techniques for enhancing drug solubility. It begins with an introduction to factors affecting drug solubility and processes of solubilization. Then it describes techniques such as co-solvency, use of surfactants, complexation, and solid state manipulation. Co-solvency uses water-miscible solvents to improve drug solubility. Surfactants form micelles above the critical micelle concentration that can solubilize drugs. Complexation with cyclodextrin can enhance aqueous solubility. Manipulating a drug's solid state, such as forming polymorphs, can also increase solubility. The document provides examples and mechanisms for each solubility enhancement technique.
This document discusses key concepts in preformulation testing. It begins by defining preformulation as investigating the physical and chemical properties of a drug substance alone and combined with excipients. The overall goal is to generate information useful for developing stable and safe dosage forms.
It then outlines some of the main steps in preformation process including assessing organoleptic properties, purity, particle size, melting point, stability, excipient compatibility, solubility, polymorphism, pH and salt formation. Specific tests are mentioned for many of these areas.
The document emphasizes that preformulation is important for aiding drug candidate selection, product design, decreasing time to market, and ensuring overall safety and efficacy of the final product
The three main rate limiting steps in drug absorption from oral solid dosage forms are disintegration, dissolution, and gastric emptying. Disintegration involves the breakdown of the solid dosage form into smaller particles so that the drug can be released. Dissolution is the process by which the drug becomes dissolved in water to be absorbed. Gastric emptying determines how quickly the drug formulation moves from the stomach into the intestines, where most absorption occurs. Several drug and formulation properties can impact these steps and influence overall drug absorption.
The document discusses the pH partition theory of drug absorption from the gastrointestinal tract. The theory states that a drug's absorption is governed by its dissociation constant (pKa), the lipid solubility of its unionized form, and the pH of the absorption site. According to the theory, only the unionized form of an acid or base drug can be absorbed if it is sufficiently lipid soluble. The fraction of a drug in its unionized form depends on the drug's pKa and the pH of the solution based on the Henderson-Hasselbalch equation. While the pH partition theory explains many observations, it has limitations such as not accounting for the presence of an unstirred water layer and virtual membrane pH at the absorption
This presentation summarizes various dissolution testing apparatus. It describes 7 types of apparatus recognized by USP, IP, BP and EP. The first four apparatus are commonly used and include the rotating basket, paddle, reciprocating cylinder and flow through cell. The presentation provides details on the design, working, and typical uses of each apparatus type. It also discusses commonly used dissolution media and concludes that the goal of dissolution testing is to ensure pharmaceutical quality and understand biopharmaceutical properties like rate and extent of drug absorption.
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.
Preformulation testing involves investigating a drug's physical and chemical properties alone and with excipients. This helps formulators develop stable and bioavailable dosage forms. Tests examine properties like solubility, stability, and purity which provide information on developing solid dosage forms. Understanding these properties is the first step in rational drug development.
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT DESIGNN Anusha
BIOPHARMACEUTICS studies the in vitro impact of physicochemical properties of drugs and drug products on delivery to body under normal or pathologic conditions.
Biopharmaceutics links the physical and chemical properties of drug and drug product to their performance, in vivo.
The aim of biopharmaceutics is to adjust the delivery of drug from drug products in such a manner as to provide: optimal therapeutic activity and safety for the patient.
Preformulation studies characterize the physical and chemical properties of drug substances to aid in developing stable, safe, and effective drug formulations with high bioavailability. Key aspects of preformulation studies include characterizing the bulk properties, solubility, and stability of drugs. This involves investigating properties like crystallinity, polymorphism, particle size, density, and how these properties influence solubility, stability, and bioavailability when formulated into drug products. The goal is to obtain information early in development to guide decisions around formulation components, manufacturing processes, analytical methods, and dosage forms.
This document describes the various types of dissolution apparatus as specified by the USP, IP, and BP. It outlines 7 types of USP apparatus including the basket, paddle, reciprocating cylinder, flow through cell, paddle over disc, rotating cylinder, and reciprocating disc. The basket and paddle types are also included in the IP and BP. The key features and uses of each apparatus are provided along with diagrams. Ideal features of dissolution apparatus include precise specifications, simple design, sensitivity to changes, maintenance of sink conditions, and minimal dosage form abrasion.
Preformulation studies for bulk characterizationmangu3107
The document discusses preformulation studies, which generate information to help formulate stable and effective drug dosage forms. The overall goals of preformulation are to improve drug stability, bioavailability, and reduce incompatibility. Some key tests described include determining the drug's physical properties like color, odor, taste, purity, and thermal behavior. Melting point analysis can provide information on a drug's identity and purity. Preformulation studies are important to identify suitable drug candidates and formulations before clinical development.
This document provides an overview of preformulation factors affecting dosage forms. It discusses properties like flow, density, compressibility, and others that influence the development of safe and effective drug dosage forms. The goal of preformulation is to design dosage forms with good bioavailability. Various methods for characterizing properties are described, along with their importance in determining the suitable dosage form for a drug.
A co solvent system is one in which a water miscible or partially miscible organic solvent is mixed with water to form a modified aqueous solution. And the phenomenon called Cosolvency
cosolvents have some degree of hydrogen bond donating and or hydrogen bond accepting ability as well as small hydrocarbon regions.
The resulting solution will have physical properties that are intermediate to that of the pure organic solvent and water through the reduction of water–water interaction.
This document discusses large volume parenterals (LVPs), which are intravenous solutions intended for administration of more than 100 mL. It describes the characteristics, containers, labeling requirements, commonly used solutions like sodium chloride, dextrose, Ringer's solution and lactated Ringer's solution. It also discusses types of LVPs including electrolyte, carbohydrate, and nutritional solutions. Large volume parenteral containers can be plastic bags or glass bottles. Total parenteral nutrition solutions, cardioplegia solutions, peritoneal dialysis solutions, and irrigating solutions are also summarized. Formulation considerations for LVPs like drug-excipient compatibility, selection of containers, solubility of active ingredients, and pH are highlighted.
This document provides information about tablets as a drug delivery system. It defines tablets and describes their key components and manufacturing process. Tablets consist of active pharmaceutical ingredients and excipients that control release and aid manufacturing. Excipients include fillers, disintegrants, binders, lubricants and others. Tableting involves powder compression in a die and punch press. Tablets offer benefits like precision dosing but some drugs are not suitable. Quality is ensured through testing dissolution and other properties.
The document discusses various methods to improve drug solubility including physical modifications like particle size reduction through micronization or formation of nanosuspensions, modification of crystal habit through polymorphism, and drug dispersion in carriers through techniques like solid dispersions. It also discusses chemical modifications such as changing pH, use of buffers, and derivatization. Other methods covered are complexation, solubilization by surfactants to form microemulsions, co-crystallization, cosolvency, hydrotrophy, and solvent deposition. The biopharmaceutical classification system relating solubility and permeability to drug absorption is also summarized.
The document provides an overview of drug dissolution including:
- Definitions of dissolution rate and intrinsic dissolution rate.
- Theories of drug dissolution including the diffusion layer model, Danckwert's model, and the interfacial barrier model.
- Factors that affect drug dissolution related to the physicochemical properties of drugs, drug product formulation, processing factors, dissolution apparatus and test parameters.
- Importance and applications of drug dissolution testing in product development, quality assurance, stability assessment, and biowaivers.
This document discusses drug stability and factors that affect it. It defines drug stability as a drug product remaining within established specifications for identity, strength, quality and purity. Factors like temperature, humidity, light and microbial contamination can cause drug degradation through chemical, physical and biological processes like hydrolysis, oxidation and photolysis. The document outlines various packaging materials and how they can impact stability. It also describes different types of stability studies conducted, including long-term real-time testing and accelerated methods like elevated temperature to evaluate products' shelf lives under normal conditions.
The document discusses parenteral dosage forms. Parenterals are sterile solutions or suspensions of drugs administered directly into veins, muscles, or under the skin. They do not utilize the alimentary canal and must meet general requirements including stability, sterility, isotonicity, and being free of pyrogens, toxins, and foreign particles. Evaluation tests for parenterals include sterility, pyrogen, clarity, and leakage tests.
This document discusses biopharmaceutical factors that can affect the bioavailability of drugs. It focuses on pharmaceutical factors including physicochemical properties of drug molecules and dosage form characteristics. Physicochemical properties like solubility, dissolution rate, particle size, polymorphism, salt form, and ionization state can impact drug absorption. The pH-partition hypothesis explains how a drug's pKa and lipid solubility relate to absorption based on gastrointestinal pH. Dosage form properties such as disintegration time, manufacturing methods, and ingredients are also discussed as formulation factors influencing bioavailability.
This document discusses dissolution testing of pharmaceutical dosage forms. It describes the types of dissolution apparatuses, including basket, paddle, reciprocating cylinder, flow-through cell, and transdermal cell apparatuses. The key features and uses of each apparatus are outlined. Factors that influence dissolution rate, such as formulation components, processing methods, and test conditions, are also summarized. These include vehicles, diluents, disintegrants, and processing methods like granulation and compression force.
1) Solubility is the maximum amount of a substance that dissolves in a solvent to form a saturated solution at a given temperature and pressure.
2) Solubility is ideally measured at 4°C and 37°C to ensure physical stability and support biopharmaceutical evaluation. Solubility below 1 mg/ml indicates poor absorption and need for preformulation studies.
3) Preformulation solubility studies focus on the drug solvent system and include determining properties like intrinsic solubility, pH solubility profiles, effects of surfactants, and temperature dependence to understand a drug's solubility and dissolution behavior.
Pharmaceutical film coating is considered a key part in the production of solid pharmaceutical dosage forms since it gives superior organoleptic properties products. In addition, it can improve the physical and chemical stability of dosage forms, and modify the release characteristics of the drug. Several troubleshooting problems such as twinning mottling, chipping, etc., may arise during or after or even during the shelf life of the film coated dosage forms. These troubleshooting problems may be due to tablet core faults, coating formulation faults and/or coating process faults. These problems must be overcome to avoid unnecessary product problems. Film coating as well as other parts of the pharmaceutical technology is subjecting to continuous innovation. The innovation may be at different levels including pharmaceutical excipients, processes, software, guidelines and equipment. In fact, of particular note is the growing interest in process analytical technology, quality by design, continuous coating processing and the inclusion of new ready for use coating formulations. In this review, we tried to explore and discuss the status of pharmaceutical film coating, the challenges that face this manufacturing process and the latest technological advances in this important manufacturing process.
This document presents information on preformulation studies, which involve characterizing the physicochemical properties of new drug molecules. The objectives are to generate stability and bioavailability data for formulation development. Key studies discussed include analyzing bulk properties, solubility, partitioning, hygroscopicity, ionization, dissolution, stability, and compatibility. Analytical techniques like spectroscopy, microscopy, thermal analysis, and chromatography are used to investigate properties and purity. Thorough preformulation provides critical information for designing dosage forms that are stable, safe, and effective.
The document discusses preformulation and summarizes some of its key aspects. Preformulation involves determining the physicochemical properties of new drug substances to aid in developing effective dosage forms. It covers topics like organoleptic properties, purity, particle size and shape, solubilization using surfactants, and the effect of temperature, pH and co-solvents on solubility. It also mentions the importance of preformulation stability studies and considering drug characteristics for different dosage forms. The goals of preformulation are establishing parameters, kinetic profiles, physical characteristics and compatibility with excipients.
Preformulation testing involves investigating a drug's physical and chemical properties alone and with excipients. This helps formulators develop stable and bioavailable dosage forms. Tests examine properties like solubility, stability, and purity which provide information on developing solid dosage forms. Understanding these properties is the first step in rational drug development.
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT DESIGNN Anusha
BIOPHARMACEUTICS studies the in vitro impact of physicochemical properties of drugs and drug products on delivery to body under normal or pathologic conditions.
Biopharmaceutics links the physical and chemical properties of drug and drug product to their performance, in vivo.
The aim of biopharmaceutics is to adjust the delivery of drug from drug products in such a manner as to provide: optimal therapeutic activity and safety for the patient.
Preformulation studies characterize the physical and chemical properties of drug substances to aid in developing stable, safe, and effective drug formulations with high bioavailability. Key aspects of preformulation studies include characterizing the bulk properties, solubility, and stability of drugs. This involves investigating properties like crystallinity, polymorphism, particle size, density, and how these properties influence solubility, stability, and bioavailability when formulated into drug products. The goal is to obtain information early in development to guide decisions around formulation components, manufacturing processes, analytical methods, and dosage forms.
This document describes the various types of dissolution apparatus as specified by the USP, IP, and BP. It outlines 7 types of USP apparatus including the basket, paddle, reciprocating cylinder, flow through cell, paddle over disc, rotating cylinder, and reciprocating disc. The basket and paddle types are also included in the IP and BP. The key features and uses of each apparatus are provided along with diagrams. Ideal features of dissolution apparatus include precise specifications, simple design, sensitivity to changes, maintenance of sink conditions, and minimal dosage form abrasion.
Preformulation studies for bulk characterizationmangu3107
The document discusses preformulation studies, which generate information to help formulate stable and effective drug dosage forms. The overall goals of preformulation are to improve drug stability, bioavailability, and reduce incompatibility. Some key tests described include determining the drug's physical properties like color, odor, taste, purity, and thermal behavior. Melting point analysis can provide information on a drug's identity and purity. Preformulation studies are important to identify suitable drug candidates and formulations before clinical development.
This document provides an overview of preformulation factors affecting dosage forms. It discusses properties like flow, density, compressibility, and others that influence the development of safe and effective drug dosage forms. The goal of preformulation is to design dosage forms with good bioavailability. Various methods for characterizing properties are described, along with their importance in determining the suitable dosage form for a drug.
A co solvent system is one in which a water miscible or partially miscible organic solvent is mixed with water to form a modified aqueous solution. And the phenomenon called Cosolvency
cosolvents have some degree of hydrogen bond donating and or hydrogen bond accepting ability as well as small hydrocarbon regions.
The resulting solution will have physical properties that are intermediate to that of the pure organic solvent and water through the reduction of water–water interaction.
This document discusses large volume parenterals (LVPs), which are intravenous solutions intended for administration of more than 100 mL. It describes the characteristics, containers, labeling requirements, commonly used solutions like sodium chloride, dextrose, Ringer's solution and lactated Ringer's solution. It also discusses types of LVPs including electrolyte, carbohydrate, and nutritional solutions. Large volume parenteral containers can be plastic bags or glass bottles. Total parenteral nutrition solutions, cardioplegia solutions, peritoneal dialysis solutions, and irrigating solutions are also summarized. Formulation considerations for LVPs like drug-excipient compatibility, selection of containers, solubility of active ingredients, and pH are highlighted.
This document provides information about tablets as a drug delivery system. It defines tablets and describes their key components and manufacturing process. Tablets consist of active pharmaceutical ingredients and excipients that control release and aid manufacturing. Excipients include fillers, disintegrants, binders, lubricants and others. Tableting involves powder compression in a die and punch press. Tablets offer benefits like precision dosing but some drugs are not suitable. Quality is ensured through testing dissolution and other properties.
The document discusses various methods to improve drug solubility including physical modifications like particle size reduction through micronization or formation of nanosuspensions, modification of crystal habit through polymorphism, and drug dispersion in carriers through techniques like solid dispersions. It also discusses chemical modifications such as changing pH, use of buffers, and derivatization. Other methods covered are complexation, solubilization by surfactants to form microemulsions, co-crystallization, cosolvency, hydrotrophy, and solvent deposition. The biopharmaceutical classification system relating solubility and permeability to drug absorption is also summarized.
The document provides an overview of drug dissolution including:
- Definitions of dissolution rate and intrinsic dissolution rate.
- Theories of drug dissolution including the diffusion layer model, Danckwert's model, and the interfacial barrier model.
- Factors that affect drug dissolution related to the physicochemical properties of drugs, drug product formulation, processing factors, dissolution apparatus and test parameters.
- Importance and applications of drug dissolution testing in product development, quality assurance, stability assessment, and biowaivers.
This document discusses drug stability and factors that affect it. It defines drug stability as a drug product remaining within established specifications for identity, strength, quality and purity. Factors like temperature, humidity, light and microbial contamination can cause drug degradation through chemical, physical and biological processes like hydrolysis, oxidation and photolysis. The document outlines various packaging materials and how they can impact stability. It also describes different types of stability studies conducted, including long-term real-time testing and accelerated methods like elevated temperature to evaluate products' shelf lives under normal conditions.
The document discusses parenteral dosage forms. Parenterals are sterile solutions or suspensions of drugs administered directly into veins, muscles, or under the skin. They do not utilize the alimentary canal and must meet general requirements including stability, sterility, isotonicity, and being free of pyrogens, toxins, and foreign particles. Evaluation tests for parenterals include sterility, pyrogen, clarity, and leakage tests.
This document discusses biopharmaceutical factors that can affect the bioavailability of drugs. It focuses on pharmaceutical factors including physicochemical properties of drug molecules and dosage form characteristics. Physicochemical properties like solubility, dissolution rate, particle size, polymorphism, salt form, and ionization state can impact drug absorption. The pH-partition hypothesis explains how a drug's pKa and lipid solubility relate to absorption based on gastrointestinal pH. Dosage form properties such as disintegration time, manufacturing methods, and ingredients are also discussed as formulation factors influencing bioavailability.
This document discusses dissolution testing of pharmaceutical dosage forms. It describes the types of dissolution apparatuses, including basket, paddle, reciprocating cylinder, flow-through cell, and transdermal cell apparatuses. The key features and uses of each apparatus are outlined. Factors that influence dissolution rate, such as formulation components, processing methods, and test conditions, are also summarized. These include vehicles, diluents, disintegrants, and processing methods like granulation and compression force.
1) Solubility is the maximum amount of a substance that dissolves in a solvent to form a saturated solution at a given temperature and pressure.
2) Solubility is ideally measured at 4°C and 37°C to ensure physical stability and support biopharmaceutical evaluation. Solubility below 1 mg/ml indicates poor absorption and need for preformulation studies.
3) Preformulation solubility studies focus on the drug solvent system and include determining properties like intrinsic solubility, pH solubility profiles, effects of surfactants, and temperature dependence to understand a drug's solubility and dissolution behavior.
Pharmaceutical film coating is considered a key part in the production of solid pharmaceutical dosage forms since it gives superior organoleptic properties products. In addition, it can improve the physical and chemical stability of dosage forms, and modify the release characteristics of the drug. Several troubleshooting problems such as twinning mottling, chipping, etc., may arise during or after or even during the shelf life of the film coated dosage forms. These troubleshooting problems may be due to tablet core faults, coating formulation faults and/or coating process faults. These problems must be overcome to avoid unnecessary product problems. Film coating as well as other parts of the pharmaceutical technology is subjecting to continuous innovation. The innovation may be at different levels including pharmaceutical excipients, processes, software, guidelines and equipment. In fact, of particular note is the growing interest in process analytical technology, quality by design, continuous coating processing and the inclusion of new ready for use coating formulations. In this review, we tried to explore and discuss the status of pharmaceutical film coating, the challenges that face this manufacturing process and the latest technological advances in this important manufacturing process.
This document presents information on preformulation studies, which involve characterizing the physicochemical properties of new drug molecules. The objectives are to generate stability and bioavailability data for formulation development. Key studies discussed include analyzing bulk properties, solubility, partitioning, hygroscopicity, ionization, dissolution, stability, and compatibility. Analytical techniques like spectroscopy, microscopy, thermal analysis, and chromatography are used to investigate properties and purity. Thorough preformulation provides critical information for designing dosage forms that are stable, safe, and effective.
The document discusses preformulation and summarizes some of its key aspects. Preformulation involves determining the physicochemical properties of new drug substances to aid in developing effective dosage forms. It covers topics like organoleptic properties, purity, particle size and shape, solubilization using surfactants, and the effect of temperature, pH and co-solvents on solubility. It also mentions the importance of preformulation stability studies and considering drug characteristics for different dosage forms. The goals of preformulation are establishing parameters, kinetic profiles, physical characteristics and compatibility with excipients.
The document discusses preformulation in pharmacy. Preformulation involves characterizing the physical and chemical properties of a drug substance alone and when combined with excipients. It aims to generate information for developing stable and bioavailable dosage forms. The key steps in preformulation include assessing properties like solubility, stability, solid state compatibility, physico-chemical characteristics, and in vitro availability. Organoleptic properties like color, odor, taste, shape and size are also evaluated to understand sensory characteristics.
Grade 8 Integrated Science Chapter 10 Lesson 1 on substances and mixtures. Understanding pure substances and homogeneous and heterogeneous mixtures. Identifying substances from mixtures.
selection of dissolution medium And dissolution study of solid dosage formAshwin Patil
The document discusses dissolution testing of solid oral dosage forms. It covers selection of dissolution media based on factors like drug solubility and formulation type. Common dissolution media include simulated gastric fluid, water and simulated intestinal fluid. Selection of parameters like rpm, time and apparatus depends on the formulation. Dissolution testing is important for quality control and bioequivalence studies. It provides insight into in vivo performance and helps product development.
The document summarizes a seminar presentation on parenterals. Parenterals are sterile preparations that are administered through non-oral routes such as injection. The key routes of administration are subcutaneous, intramuscular, and intravenous injection. Parenterals offer advantages of quick onset of action and are suitable when oral administration is not possible, but have disadvantages like pain on injection and risk of allergic reactions. The document outlines the formulation, manufacturing, packaging, and quality control processes to ensure the sterility and safety of parenteral products.
Preformulation testing of solid dosage formsGaurav Kr
The document discusses preformulation testing, which is the first step in developing solid dosage forms and involves investigating a drug's physical and chemical properties alone and with excipients to generate useful information for formulating stable and bioavailable dosage forms. It outlines various characterization tests and properties that should be evaluated including solubility, particle size, purity, and surface area to guide formulation development and ensure batch-to-batch consistency.
Parenterals are sterile solutions or suspensions of drugs administered through routes other than the gastrointestinal tract. This document discusses various aspects of parenterals including their routes of administration, requirements for stability and sterility, and types such as small volume parenterals and large volume parenterals. It provides details on the production of water for injection and various parenteral vehicles, formulations, and examples.
This document discusses pharmaceutical preformulation. It notes that preformulation characterizes drug substance properties like solubility, dissolution, stability and evaluates parameters like pKa. Thorough preformulation is important for developing robust formulations. The document outlines how preformulation fits within the overall drug development process and highlights the importance of solubility determination and challenges with poorly soluble compounds. It also discusses classification systems like BCS and factors affecting solubility.
Importance of partition coefficient, solubility and dissociation on pre-formu...SHANE_LOBO145
This document discusses the importance of preformulation studies, specifically focusing on partition coefficient, dissociation constant, and solubility. It defines these key terms and explains their significance in determining drug absorption and developing drug formulations. The partition coefficient indicates a drug's lipophilicity and ability to cross cell membranes. The dissociation constant and Henderson-Hasselbalch equation are used to predict drug ionization and site of absorption in the gastrointestinal tract. Solubility is critical for bioavailability and influences formulation strategies to increase or decrease a drug's aqueous solubility. Understanding these physicochemical properties is essential for designing an optimal drug delivery system.
The document discusses the Biopharmaceutical Classification System (BCS), which classifies drug substances based on their aqueous solubility and intestinal permeability. The BCS has four classes based on whether a drug is highly soluble/permeable or low soluble/permeable. It provides a framework to determine if in vitro dissolution tests can replace bioequivalence studies for certain drugs. The BCS considers factors like dose/solubility ratios, dissolution rates, and permeability to classify drugs and determine regulatory applications like biowaivers for bioequivalence studies.
DISSOLUTION
Dissolution is defined as a process in which a solid substance solubilises in a given solvent.
(i.e. mass transfer from the solid surface to the liquid phase.)
Three Theories:
Diffusion layer model / Film theory
Danckwert’s model / Penetration or Surface renewal theory
Interfacial barrier model / Double barrier or Limited solvation theory
The document discusses the applications of pharmacokinetics in new drug development, dosage form design, and novel drug delivery systems (NDDS). It covers key topics such as:
1) How pharmacokinetic principles can be applied to the design and development of new drugs, controlled release formulations, and the selection of appropriate routes of administration.
2) The important pharmacokinetic parameters used in characterization and the approaches used for dosage regimen design.
3) How pharmacokinetics can aid in formulation development, bioavailability/bioequivalence testing, and the development of various NDDS.
4) Considerations for dosing adjustments based on patient factors like obesity, age, hepatic or renal impairment
This document outlines a generic product development process consisting of 7 stages: product planning, concept development, system-level design, detail design, testing and refinement, production ramp-up, and product launch. It describes each stage in the process, from developing an initial mission statement to launching the final product. The process transforms inputs like market needs and a mission statement into a finished product through stages of conceptualization, design, testing, and production preparation.
This document discusses the determination of partition coefficients of drug molecules and its importance in preformulation studies. The partition coefficient is the ratio of concentrations of a compound between two immiscible liquids, such as octanol and water, at equilibrium. It is a measure of how hydrophilic or lipophilic a compound is. Determining the partition coefficient provides useful information for developing stable and bioavailable dosage forms as it influences a drug's absorption and distribution in the body. Common methods to determine the partition coefficient include the shake flask method and HPLC. The coefficient affects pharmacokinetic properties like ADME and is an important consideration in preformulation to optimize drug delivery.
This document provides an overview of parenterals (injectable drugs), including:
- Definitions and routes of administration for parenterals
- General requirements like vehicles, additives, and ensuring isotonicity
- Methods for sterilization, formulation, packaging, and quality control testing of parenterals
- Considerations for facilities and production areas to ensure sterility during manufacturing
It discusses key aspects of developing parenteral drugs like pre-formulation studies, adjustment of tonicity, and precautions for aseptic work. Common sterilization techniques and packaging materials are outlined. Quality control tests evaluated include leakage, clarity, sterility, and pyrogen testing. Overall, the document serves as an introduction
Plant layout refers to the configuration and placement of departments, work centers, equipment, and the flow of materials through the production process. Layout decisions are important because they require substantial investments, involve long-term commitments, and significantly impact costs and efficiency. The main types of layouts are product layouts which focus on smooth material flow, process layouts which group similar machinery together, and combination layouts which blend aspects of both. The objective is to facilitate smooth and efficient material and information flow while minimizing costs and non-value added activities.
This document provides guidance on preformulation studies for new drug substances. It outlines the key steps in preclinical testing including pharmacology, toxicology, and preformulation. Preformulation involves characterizing the physicochemical properties of the drug, including solubility, pKa, partition coefficient, stability, and crystal properties. The goal is to design an optimal drug delivery system through understanding the physical and chemical attributes of the new molecule.
The document provides an overview of preformulation studies, which are conducted to determine the physicochemical properties of new drug substances prior to formulation development. Key aspects covered include definition of preformulation, factors considered, objectives, outcomes, common tests like solubility and stability studies, and techniques involved. Specifically, the document discusses solubility analysis methods, factors affecting solubility like pH and temperature, and importance of solubility determination. It also covers common degradation pathways like oxidation and hydrolysis, and approaches to prevent or minimize degradation.
The document discusses preformulation studies that are conducted prior to developing a dosage form for a new drug. The objectives are to determine the drug's physicochemical properties, solubility, stability, and compatibility with excipients. Key tests include solubility studies under various conditions, stability studies of solid and liquid states under stress conditions like heat, light and pH, and chemical characterization of properties like oxidation and hydrolysis. The outcomes aim to develop a formulation that safely delivers the drug to the site of action as intended.
This document provides an overview of preformulation studies, which characterize the physical and chemical properties of new drug molecules to aid in the development of safe, effective, and stable dosage forms. Some key points covered include:
- Preformulation studies give direction for dosage form selection, excipient choice, composition, and process development.
- Important physicochemical properties to determine include solubility, partition coefficient, pKa, stability, and interactions with excipients.
- Methods are described for evaluating properties like solubility, dissolution, oxidation, hydrolysis, and polymorphism which can impact stability and bioavailability.
- Understanding these properties aids in developing robust formulations and setting appropriate storage conditions for drug products
1) Preformulation solubility studies focus on understanding a drug candidate's solubility profile and solubilization mechanisms to provide a basis for later formulation work. Key factors studied include pH, temperature, ionic strength, and buffer concentrations.
2) Analytical methods like HPLC, UV/visible spectroscopy, and gas chromatography are useful for solubility measurements. Determining a drug's pKa is also important to understand how solubility may change with pH.
3) Temperature, pH, common ion effects, and cosolvents can all impact a drug's solubility and dissolution rate, which are important considerations for bioavailability.
solubility enhancement and cosolvency by madhavishaikhazaroddin
This document provides an overview of solubility enhancement and cosolvency. It begins with definitions of solubility enhancement and cosolvency as using water-miscible solvents to increase the solubility of weak electrolytes and nonpolar molecules. Common cosolvents like ethanol, propylene glycol, and polyethylene glycol are discussed. The mechanisms of how cosolvents increase solubility by changing dielectric constant and promoting hydrogen bonding are explained. Several methods for solubility enhancement are reviewed, including particle size reduction, use of surfactants, solid dispersions, and pH adjustment. The document concludes that various techniques can be combined to improve solubility of poorly soluble drugs based on their properties, with the goal of improving bioavailability
Preformulation involves characterizing the physical and chemical properties of new drug molecules to aid in developing safe and stable dosage forms. It provides direction for choosing the dosage form, excipients, composition and process development. Key factors studied include the drug's physical characteristics like crystallinity, hygroscopicity and solubility, as well as its chemical stability when exposed to conditions like oxidation, hydrolysis and photolysis. Understanding how the drug behaves under various conditions helps ensure the dosage form maintains integrity during storage and use.
This document discusses excipients and their role in drug formulations. It notes that excipients are ingredients other than the active pharmaceutical ingredient that are used to formulate dosage forms. Excipients can act as protective agents, bulking agents, and can improve drug bioavailability. The document then lists common types of excipients and potential interactions between drugs and excipients, such as physical, chemical, biopharmaceutical, and excipient-excipient interactions. It describes several analytical techniques used to detect drug-excipient interactions, including DSC, accelerated stability studies, FT-IR, DRS, chromatography methods, and others.
The document discusses various models of drug transport across biological membranes including permeability, solubility, and the pH partition hypothesis. It explains that for a drug to be efficiently absorbed, it needs to be in its uncharged form at the membrane surface. The pH partition hypothesis states that drug absorption depends on the fraction of uncharged drug molecules, which is determined by the drug's pKa and the pH of the absorption site. However, the pH partition theory is an oversimplification and deviations can occur based on additional factors like binding and solubility.
Transport models : Permeability , solubility , charge state amd the ph partit...NishaN19p7504
this topic is all about influence of ph on drug solubilty and permeability , henderson hasselbalch equation , PH partition hypothesis and its deviations
The document discusses key concepts relating to drug permeability and solubility, including the pH partition hypothesis. The pH partition hypothesis states that for optimal passive diffusion, a drug needs to be in its uncharged form at the membrane surface. The proportion of uncharged drug depends on factors like pH, solubility, and binding. Deviations from ideal pH-dependent permeability are often seen in practice. Drug absorption also depends on solubility and lipophilicity, with more lipid-soluble uncharged forms generally being better absorbed.
The movement of molecules from one phase to another is called partitioning.
If two immiscible phases are placed adjacent to each other, the solute will distribute itself between two immiscible phases until equilibrium is attained; therefore no further transfer of solute occurs.
Dissolution by Dr. Neeraj Mishra professor pharmaceuticsNeeraj Mishra
The document discusses dissolution, which is the process by which a solid substance enters the solvent phase to form a solution. Dissolution is important for drug absorption from oral dosage forms and can be the rate-limiting step. Dissolution testing is used for quality control, formulation development, and correlating in vitro dissolution to in vivo bioavailability. Theories of dissolution include diffusion layer models and surface renewal models. Factors that affect dissolution include drug properties, dosage form factors, particle size, polymorphism, salt formation, and lipid solubility.
The document discusses a study on enhancing the solubility of loratadine, a class II drug with low solubility and high permeability, through solid dispersion techniques. Loratadine's solubility decreases with increasing pH. The study prepares solid dispersions of loratadine with β-cyclodextrin, HPC, and PEG-6000 and finds their solubility is greatly improved, especially at higher pH levels. Solubility is tested in buffers from pH 1.2 to 7.4. The co-precipitation method provides better solubility results than physical mixing for the dispersions tested.
This document summarizes a study that used the liquisolid technique to enhance the dissolution rate of the poorly water soluble drug ketoprofen. Several liquisolid tablet formulations were prepared using ketoprofen as the drug and propylene glycol or tween 80 as liquid vehicles. Microcrystalline cellulose and dicalcium phosphate were used as carriers and silica gel as the coating material. The liquisolid tablets showed improved flow properties and higher drug release compared to marketed ketoprofen tablets. X-ray diffraction and FTIR analysis indicated no drug-excipient interactions. The liquisolid technique was effective in enhancing the dissolution of the poorly soluble drug ketoprofen.
This document discusses various preformulation techniques used to improve the solubility and dissolution rate of poorly soluble drugs. It describes solubilization methods like surfactants, pH adjustment, cosolvency and solid dispersions using carriers like β-cyclodextrin. Key factors that influence dissolution like temperature, surface area, and hydrodynamics based on the Noyes-Whitney equation are also covered. The importance of preformulation properties like pKa, solubility and polymorphism on drug development are highlighted. References on industrial pharmacy and pharmaceutical dosage forms are listed for further reading.
This document discusses factors that affect drug absorption from the gastrointestinal tract. It describes absorption as the movement of unchanged drug from the site of administration to systemic circulation or plasma. The main physico-chemical factors discussed are drug solubility, dissolution rate, particle size and effective surface area, salt forms of drugs, and lipophilicity. It also mentions the importance of drug stability in the GI tract for ensuring bioavailability.
3-Introduction to pharmaceutical Chemistry-and physicochemical properties (3)...HelmyFauz
Pharmachemistry is the science at the intersection of chemistry and pharmacology involved with designing, synthesizing, and developing pharmaceutical drugs. It deals with discovering new therapeutic chemicals and developing them into medicines. Pharmachemists study how to make new compounds, determine their biological effects, optimize their structure for efficacy and safety, and examine how drugs are absorbed, distributed, metabolized, and excreted. Drug activity can be structurally specific, depending on interactions with cellular receptors, or non-specific, relating to physical properties like solubility.
3-Introduction to pharmaceutical Chemistry-and physicochemical properties (3)...HelmyFauz
Pharmachemistry is the science at the intersection of chemistry and pharmacology involved with designing, synthesizing, and developing pharmaceutical drugs. It deals with discovering new therapeutic chemicals and developing them into medicines. Pharmachemists study how to make new compounds, determine their biological effects, optimize their structure for efficacy and safety, and examine how drugs are absorbed, distributed, metabolized, and excreted. Drug activity can be structurally specific, depending on interactions with cellular receptors, or non-specific, relating to physical properties like solubility.
The document discusses the objectives and importance of drug stability studies. The key objectives are to determine shelf life, provide safety and optimum storage conditions, and select primary packaging. Stability studies help predict expiry periods and gather preformulation information to produce stable products. The document also covers various chemical degradation pathways like hydrolysis, oxidation, decarboxylation, and their prevention methods.
Dr. Rakesh Kumar Sharma is an experienced pharmacy professional with over 18 years of teaching experience in India and internationally. He holds a PhD in Pharmaceutics from OPJS University and has qualifications including an MPharm and BPharm. He has worked in leadership roles in India and Saudi Arabia and has experience teaching courses in pharmaceutics, pharmaceutical technology, and industrial pharmacy. He is proficient in English with an IELTS score of 7.5. His expertise includes pharmaceutical research, formulation development, and guidance of student research projects.
The document discusses process validation for pharmaceutical manufacturing. It provides details on validation master planning, organizing validation work, process characterization, validation protocols, qualification of facilities and equipment, and validation options like prospective, concurrent and retrospective validation. Specific processes like wet granulation, tableting and coating are also discussed with parameters to consider for validation.
The document discusses the regulatory process for new drugs, including:
1) A new drug application (NDA) must be submitted and approved before marketing a new drug, as it may be considered new due to composition, use, dosage, or form.
2) An investigational new drug (IND) application is submitted for clinical trials, including preclinical animal testing and three phases of human trials to test safety, efficacy, and dosing.
3) Upon completing clinical trials, an NDA is submitted with detailed reports and the FDA may approve marketing. Significant changes later require a supplemental NDA.
The document discusses pharmaceutical packaging and describes various packaging materials and closure systems used. It covers characteristics of glass and plastic containers, types of closures, tamper resistance, and quality control tests for plastic packaging. The selection of packaging begins by determining the product's needs and marketing requirements to adequately preserve integrity.
The document discusses the design and layout considerations for pharmaceutical manufacturing facilities. It states that premises should be located to minimize risks of cross-contamination from external sources. The interior surfaces should be smooth and allow for easy cleaning. Specific areas for different processes like manufacturing, packaging, laboratories should be separated but laid out in a logical flow. Material and personnel flow should be organized to prevent mix-ups and cross-contamination. Tables and figures provide examples of suitable layouts for manufacturing tablets and liquid oral preparations.
The document discusses tablet coating processes and components, including the decision factors for coating tablets, the main components of coating (tablet properties, coating process, and coating compositions), common coating equipment and processes, film forming materials and other additives used in coatings, quality control of coated tablets, potential film defects, and the sugar coating process.
Microencapsulation involves coating small particles or droplets to form microcapsules. It can be used to modify drug release timing and mask tastes. Various coating materials can be used depending on the product requirements. Common microencapsulation methods include spray drying, fluidized bed coating, pan coating, coacervation, and solvent evaporation. These methods use different processes but generally involve applying a coating and hardening it to form microcapsules encapsulating core materials. Microencapsulation offers various applications in pharmaceutical products.
Assessment and Planning in Educational technology.pptxKavitha Krishnan
In an education system, it is understood that assessment is only for the students, but on the other hand, the Assessment of teachers is also an important aspect of the education system that ensures teachers are providing high-quality instruction to students. The assessment process can be used to provide feedback and support for professional development, to inform decisions about teacher retention or promotion, or to evaluate teacher effectiveness for accountability purposes.
Physiology and chemistry of skin and pigmentation, hairs, scalp, lips and nail, Cleansing cream, Lotions, Face powders, Face packs, Lipsticks, Bath products, soaps and baby product,
Preparation and standardization of the following : Tonic, Bleaches, Dentifrices and Mouth washes & Tooth Pastes, Cosmetics for Nails.
Macroeconomics- Movie Location
This will be used as part of your Personal Professional Portfolio once graded.
Objective:
Prepare a presentation or a paper using research, basic comparative analysis, data organization and application of economic information. You will make an informed assessment of an economic climate outside of the United States to accomplish an entertainment industry objective.
it describes the bony anatomy including the femoral head , acetabulum, labrum . also discusses the capsule , ligaments . muscle that act on the hip joint and the range of motion are outlined. factors affecting hip joint stability and weight transmission through the joint are summarized.
How to Manage Your Lost Opportunities in Odoo 17 CRMCeline George
Odoo 17 CRM allows us to track why we lose sales opportunities with "Lost Reasons." This helps analyze our sales process and identify areas for improvement. Here's how to configure lost reasons in Odoo 17 CRM
A Strategic Approach: GenAI in EducationPeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
A workshop hosted by the South African Journal of Science aimed at postgraduate students and early career researchers with little or no experience in writing and publishing journal articles.
2. Preformulation commences when a newly synthesized
drug shows sufficient Pharmacological activity in
animal models and warrant evaluation in human
beings.
Prior to the development of major dosage forms it is
essential that certain fundamental physical and
chemical properties of the drug molecule and other
derived properties of the drug powder are
determined.
This first learning phase is known as preformulation.
Rakesh Kumar Sharma 2
3. Before beginning the formal preformulation
programme the preformulation scientist must cover
a few factors, which includes
•The amount of drug available
•The physicochemical properties of the drug already
known
•The therapeutic category and anticipated dose of
the compound
•The development schedules
•The nature of information a formulator should
have or would like to have.
Rakesh Kumar Sharma 3
4. Table: A Typical Preformulation design is given below in
table
Rakesh Kumar Sharma 4
5. Spectroscopy
The first step in preformulation is to establish a simple
analytical method for quantitative estimation in
subsequent steps.
Most drugs absorb light in the UV wavelength (190-390
nm) as they are generally aromatic and contain double
bonds.
The absorption coefficient of the drug can be determined
by the formula
E1= AF/X
Where A= absorbance at λmax , F= dilution factor and X=
weight of drug(mg)
It is now possible to determine the concentration of drug
in any solution by measuring the absorbance.
C= AF/E1
Once the quantitative analytical method is established the
preformulation parameters are investigated in desire
order.
Rakesh Kumar Sharma 5
6. Intrinsic solubility (Cs) and Dissociation constant(pKa)
The solubility of drug in purified water, 0.1NHCl and
0.1N NaOH is determined.
A rise in solubility in acid than water suggests that
the drug is weak base.
Drug is weak acid if its solubility in NaOH is more
than in water. An increase in solubility in both acid
and alkali indicates either amphoteric substance ,
where as no change in solubility indicates non-
ionizable neutral molecule.
Rakesh Kumar Sharma 6
7. Intrinsic solubility also known as true solubility[Co] is
the solubility of unionized drug.
Phase solubility analysis is an efficient method for
determination of intrinsic solubility. The drug is
added to the fixed volume of the solvent in
increasing amount.
The conc is determined after equilibrium is attained.
A typical phase solubility diagram is shown
Rakesh Kumar Sharma 7
9. The solubility should ideally be measured at two
temperatures:
1. 4°C because the maximum density of water occurs
at 4°C.This leads to a minimum aqueous solubility.
2. 37°C to support Biopharmaceutical evaluation.
Rakesh Kumar Sharma 9
10. However, it is less likely , at early stages that the
drug is pure. As absolute purity is often in doubt it is
more accurate to determine this crucial solubility by
the use of a phase-solubility diagram .
Any deviation from the horizontal is indicative of
impurities, which a higher drug loading and its
inherent impurities either promotes or suppresses
solubility.
Rakesh Kumar Sharma 10
11. Figure: Effect of Impurities on solubility of Drug
Rakesh Kumar Sharma 11
12. Dissociation Constant [pKa]
Many drugs are weak acids or weak bases depending on
the pH, they exist as ionized or unionized species or both
in solution. The relative proportion of ionized and
unionized species of drug in solution governs its
absorption, along with pH this proportion depends on
pKa. Henderson-Hesselbalch equation establishes
following correlation among these factors
pH =pKa+log[unionized / ionized] for bases
pH= pKa + log [ionized/ unionized] for acids
Rakesh Kumar Sharma 12
13. Modified Henderson-Hesselbalch equation is more
suitable for quantitative determination of pKa
pH =pKa+log[Cs-Co / Co] for bases
pH =pKa+log[Co/Cs-Co] for acids.
For example: the intrinsic solubility [Co] of a weak base is
2mg/ml. The saturated solubility at pH 4 and pH 6 are
14.6 and 2.13 mg/ml
pka = 4+ log[14.6-2/2]= 4.799
pka = 6+ log[2.13-2/2]= 4.813.
Rakesh Kumar Sharma 13
14. Salts
A major improvement in solubility can be achieved by
forming a salt.
The consequence of changing chlordiazepoxide to
various salt forms is shown in.
Rakesh Kumar Sharma 14
15. Larger the value of pKa, the smaller the extent of
dissociation, Acid with pKa value less than 2 are
strong acids.
In some cases, salts prepared from strong acids or
bases are freely soluble but very hygroscopic. This
does lead to instability in tablet or capsule
formulations.
A less soluble salt will generally be less hygroscopic.
Rakesh Kumar Sharma 15
16. Injections should ideally lie in the pH range 3-9 to
prevent vessel or tissue damage and pain at the
injection site.
Oral syrups should not be too acidic, to enhance
palatability.
Packaging may also be susceptible: undue alkalinity
will attack glass, and hydrochloride salts should not
be used in aerosol as a propellant-acid reaction will
corrode the metal container.
Rakesh Kumar Sharma 16
17. Solvents
It is generally necessary to formulate an injection or liquid
dosage form, even if there is no intention to market. The first
choice solvent is obviously water. However, although the drug
may be freely soluble, it may be unstable in aqueous solution.
Chlordiazepoxide HCl is such an example.
Accordingly, water-miscible solvents are used:
In formulations to improve solubility or stability
Oils are used in emulsions, Topicals (creams and
ointments), intramuscular injections and liquid-fill oral
preparations (soft and hard gelatin capsules)
Rakesh Kumar Sharma 17
18. Partition coefficient
A major criterion in evaluation of the ability of a drug to penetrate the
lipid membranes within the body is its apparent oil/ water partition
coefficient, defined as
P = Co/Cw
Where
Co: equilibrium concentration of the drug in organic phase (n-octanol)
Cw: equilibrium concentration of all forms in an aqueous phase (water)
It is the measure of lipophilicity of drug(s).
There is an optimum partition coefficient for a drug in which it most
effectively permeates membranes and thus shows greatest activity.
Values of the partition coefficient below this optimum result in decreased
lipid solubility and the drug will remain localized in the first aqueous phase
it contacts.
Generally for a lipophilic drug, the partition coefficient is (log P >1)
Rakesh Kumar Sharma 18
19. Common ion effect
An often overlooked interaction is the common ion
effect. A common ion often significantly reduces the
solubility of a slightly soluble electrolyte.
Hydrochloride salts often exhibit suboptimal
solubility in gastric juice owing to the abundance of
Cl ions.
Rakesh Kumar Sharma 19
20. To identify a common ion interaction, the IDR of the
hydrochloride (or inorganic) salt should be compared
between:
• water and water containing 1.2% w/v NaCl, and
• 0.05 M HC1 and 0.9% w/v NaCl in 0.05 M HC1.
A common ion effect with Cl- will result in a
significantly reduced IDR in the presence of sodium
chloride.
Rakesh Kumar Sharma 20
21. Dissolution
The dissolution rate of a drug is only important
where it is the rate-limiting step in the absorption
process. Kaplan (1972) suggested that provided the
solubility of a drug exceeded 10 mg/ ml at pH <7, no
bioavailability- or dissolution-related problems were
to be expected. Below 1 mg /ml such problems were
quite possible, and salt formation could improve
absorption and solubility by controlling the pH of the
microenvironment independently of the drug and
dosage forms' position within the GI tract.
Rakesh Kumar Sharma 21
22. The dissolution of a drug is described by the general
Noyes – whitney equation.
dc/dt = KS (Cs-Ct)
Where dc/dt= dissolution rate
K= dissolution rate constant,
Cs= conc. of saturated diffusion layer
Ct= concentration at time t
S= surface area
The constant K is equal to D/h
Where D is the diffusion coefficient of the dissolving
solid and h is the thickness of the diffusion layer
Rakesh Kumar Sharma 22
23. W/A = kt
Where k = dissolution rate constant
And W is the weight (mg) of drug dissolve in time t
A plot of W versus t gives straight line with slope is
equal to k, this is known as intrinsic dissolution
rate (IDR) and is expressed in mg/min/cm2 .
Compounds with IDR greater than 1 mg/min/cm2
are not likely to present dissolution rate limited
absorption problems.
Rakesh Kumar Sharma 23
24. BULK CHARACTERIZATION
MELTING POINT
Techniques
The melting point of a drug can be measured using
three techniques:
1. Capillary melting
2. Hot stage microscopy
3. Differential scanning calorimetry or thermal
analysis.
Rakesh Kumar Sharma 24
25. Capillary melting
Capillary melting (the observation of melting in a
capillary tube in a heated metal block) gives
information about the melting range but it is
difficult to assign an accurate melting point.
Rakesh Kumar Sharma 25
26. Hot stage microscopy
This is the visual observation of melting under a
microscope equipped with a heated and lagged
sample stage. The heating rate is controllable and
up to three transitions can be registered. It is more
precise as the phase transitions (first melt, 50% melt
and completion) can be registered on a recorder as
the melting proceeds, and because of the high
magnification the values are more accurate.
Rakesh Kumar Sharma 26
27. Differential scanning calorimetry and thermal
analysis
The sample size require is 2-5 mg
DTA measures the temperature difference between
the sample and a reference as a function of
temperature or time when heating at a constant
rate. DSC is similar to DTA, except that the
instrument measures the amount of energy
required to keep the sample at the same
temperature as the reference, i.e. it measures the
enthalpy of transition.
Rakesh Kumar Sharma 27
28. When no physical or chemical change occurs within
the sample then there is neither a temperature
change nor input energy to maintain an isotherm.
The major concern in preformulation is
polymorphism, and the measurement of melting
point and other phase changes is the primary
diagnostic tool.
Confirmation by IR spectroscopy and X-ray
diffraction is usually required.
Rakesh Kumar Sharma 28
29. Polymorphism
A polymorph is a solid material with at least two
different molecular arrangements that give distinct
crystal species. These differences disappear in the
liquid or the vapour state. Of concern are their
relative stabilities and solubility. The highest-
melting species is generally stable; other
polymorphs are metastable and convert to the
stable form. There are also potentially large
differences in their physical properties so that they
behave as distinct chemical entities.
Rakesh Kumar Sharma 29
30. Solubility (particularly important in suspensions
and biopharmaceutically), melting point,
density, crystal shape, optical and electrical
properties and vapour pressure are often very
different for each polymorph.
The steroid progesterone has five polymorphs,
whereas the sulphonamide ;sulphabenzamide has
four polymorphs and three solvates.
Rakesh Kumar Sharma 30
31. Pseudopolymorphism (solvates)
Prior to this, the presence of solvates or false
polymorphs, sometimes (incorrectly and confusingly)
called pseudopolymorphs, should be identified, as
most polymorphs can be obtained by changing the
recrystallizing solvent.
Typical solvents inducing polymorphic change are
water, methanol, ethanol, acetone, chloroform, n-
propanol, isopropanol alcohol, w-butanol, n-
pentanol, toluene and benzene.
Rakesh Kumar Sharma 31
32. Trace levels of solvent are usual in early batches of
new drug candidates (residues from the final
crystallization). These can become molecular
additions to the crystal and change habit.
These hydrates (water) and solvates (e.g.
methanolate, ethanolate) have been confused with
true polymorphism and have led to the term
pseudopolymorphism.
Rakesh Kumar Sharma 32
33. The distinction between these false forms and true
polymorphs can be ascertained by observing the
melting behavior of the compound dispersed in silicone
oil using hot-stage microscopy.
Pseudopolymorphs will evolve a gas (steam or solvent
vapor), causing the oil to bubble. True polymorphs
merely melt, forming a second globular phase. The
temperature at which the solvent volatilizes will be close
to the boiling point of the solvent.
Rakesh Kumar Sharma 33
34. Crystalline solubility
The most important reason to determine melting
point during preformulation is crystalline solubility.
Melting point and solubility are related via the
latent heat of fusion, which is the amount of heat
generated during melting or fusion.
Rakesh Kumar Sharma 34
35. A crystal with weak bonds has a low melting point
and low heat of fusion. Conversely, a strong crystal
lattice leads to a high melting point and a high
heat of fusion. Because solubility also requires the
disruption of crystal structure to allow molecular
dispersion in the solvent, it is also influenced by
intermolecular forces.
Rakesh Kumar Sharma 35
36. Polymorphs differ in melting point and solubility.
The existence of different crystal arrangements for
the same compound inevitably leads to differences in
crystal lattice energy, as intermolecular distances will
be different in the alternative forms. This effect is
shown in Figure for riboflavin.
Rakesh Kumar Sharma 36
38. Hygroscopicity
Tablets and capsules must be hydrophilic to
facilitate wetting and the process of de-
aggregation and drug dissolution.
As a paradox they must have limited hygroscopicity
to ensure good chemical and physical stability
under all reasonable climatic conditions.
Good packaging will accommodate moisture
challenge, e.g. glass bottles, foil blisters and
dessicant.
Rakesh Kumar Sharma 38
39. Particle size analysis
Small particles are particularly important in low-
dose high-potency drug candidates,
as large particle populations are necessary to
ensure adequate blend homogeneity and for any
drug whose aqueous solubility is poor (<1 mg
m/Lt), as dissolution rate is directly proportional to
surface area (inversely proportional to particle size).
Rakesh Kumar Sharma 39
40. POWDER FLOW PROPERTIES
Carr’s Index = tapped density- poured density X 100
Tapped density
Hausner’s ratio = Tapped density/ poured density
Values less than 1.25 indicate good flow (= 20%
Carr), whereas greater than 1.25 indicates poor
flow (= 33% Carr). Between 1.25 and 1.5, added
glidant normally improves flow.
Rakesh Kumar Sharma 40
42. Drug degradation occurs by four main processes:
• Hydrolysis
• Oxidation
• Photolysis
• Trace metal catalysis.
Hydrolysis and oxidation are the most common
pathways, and in general light (c) and metal ions
catalyse a subsequent oxidative process.
Rakesh Kumar Sharma 42
43. Temperature
Thermal effects are superimposed on all four
chemical processes. Typically a 10°C increase in
temperature can produce a 2-5-fold increase in
decay. Often the increase in reaction rate with
temperature follows an Arrhenius-type relationship:
a plot of the log of the rate of reaction against the
reciprocal of absolute temperature yields a straight
line. The reaction rate can then be calculated at any
temperature and allows a prediction of shelf-life at
room temperature by extrapolation.
Rakesh Kumar Sharma 43
44. Hydrolysis
The most likely cause of drug instability is hydrolysis.
Water plays a dominant role and in many cases it is implicated
passively as a solvent vector between two reacting species in
solution.
Hydrolytic reactions involve nucleophilic attack of labile bonds,
e.g. lactam > ester > amide > imide, by water on the drug in
solution, and are first order.
When this attack is by a solvent other than water it is known as
solvolysis.
A number of conditions catalyse the breakdown:
• The presence of OH-
• The presence of H3O+
• The presence of divalent metal ions
• Ionic hydrolysis (protolysis) is quicker than molecular
• Heat
• Light
• Solution polarity and ionic strength
• High drug concentrations.
Rakesh Kumar Sharma 44
45. The Influence of pH
The degradation of most drugs is catalysed by
extremes of pH, i.e. high [H3O+] and [OH-], and
many drugs are most stable between pH 4 and 8.
Where maximum stability dictates wider values, it is
important for injections that there is low buffer
capacity to prevent unnecessary challenge to the
homeostatic pH (7.4) of blood.
Weakly acidic and basic drugs are most soluble
when ionized, and it is then that instability is most
likely as they are charged. This leads to a problem,
as
many potent drugs are extremely poorly soluble and
pH ionization is the most obvious method to obtain
a solution.
Rakesh Kumar Sharma 45
46. In some cases, therefore, the inclusion of
a water-miscible solvent in the formulation will
increase stability by:
1. Suppressing ionization
2. Reducing the extreme of pH required to achieve
solubility
3. Reducing water activity by reducing the polarity of
the solvent, e.g. 20% propylene glycol in
chlordiazepoxide HC1 injection.
Rakesh Kumar Sharma 46
47. Reactions in aqueous solution are usually catalysed
by pH, and this is monitored by measuring
degradation rates (usually pseudo first order)
against pH, keeping temperature, ionic strength
and solvent concentration constant. Suitable
buffers include acetate, citrate, lactate, phosphate
and ascorbate (an intrinsic antioxidant).
Rakesh Kumar Sharma 47
48. Solvolysis
Where the reacting solvent is not water, then
breakdown is termed solvolysis.
Phenobarbitone is considerably more stable in
preparations containing water-miscible solvents,
whereas aspirin, which undergoes extensive
hydrolysis, is degraded further by aqueous solvents.
Both effects are directly related to the dielectric
constant (polarity) of the solvent.
Rakesh Kumar Sharma 48
49. In general, if a compound produces degradation
products which are more polar then the addition of
a less polar solvent will stabilize the formulation.
If the degradation products are less polar, then the
vehicle should be more polar to improve stability.
With the hydrolysis of neutral non-polar drugs, e.g.
steroids, the transition state will be non-polar with
no net charge. In this case solvents will not affect
the rate of decomposition and can be used with
impunity to increase solubility.
Rakesh Kumar Sharma 49
50. Oxidation
Oxidation is controlled by the environment, i.e. light,
trace metals, oxygen and oxidizing agents. Reduction is
a complimentary reaction (redox) and there is a
mutual exchange of electrons. Oxidation is a loss of
electrons and an oxidizing agent must be able to take
electrons. Most antioxidants function by providing
electrons or labile H+, which will be accepted by any
free radical to terminate the chain reaction. A
prerequisite for effective antioxidant activity in any
particular preparation is that the antioxidant is more
readily oxidized than the drug.
Rakesh Kumar Sharma 50
51. Chelating agents
Chelating agents are capable of forming more than
one bond. For example, ethylene diamine is
bidentate (two links), tripyridyl is tridentate
(three) and ethylene diamine tetra-acetic acid
(EDTA) is hexadentate (six), which makes it
particularly effective as a pharmaceutical chelating
agent.
Rakesh Kumar Sharma 51
52. Photolysis
When molecules are exposed to electromagnetic
radiation they absorb light (photons) at
characteristic wavelengths which causes an increase
in energy,
which can:
• cause decomposition
• be retained or transferred
• be converted to heat
• result in light emission at a new wavelength
(fluorescence, phosphorescence).
photolysis is prevented by suitable packaging: low
actinic amber glass bottles, cardboard outers and
aluminium foil overwraps and blisters.
Rakesh Kumar Sharma 52
53. Solid-State stability
In all solid dose formulations there will be some free
moisture (contributed by excipients as well as the
drug), and certainly in tablets a significant percentage,
typically 2% w/w, is required to facilitate good
compression.
This free water acts as a vector for chemical reactions
between drug and excipients, and the adsorbed
moisture films are saturated with drug compared to the
dilute solutions encountered in injectables.
Rakesh Kumar Sharma 53
54. ASSAY DEVELOPMENT
The assumption that the drug is stable may not be
valid as drugs are notoriously unstable, particularly
as hydrolysis is often the predominant cause. In
order to follow drug stability, in both solution and
solid phase, it is mandatory to have suitable
stability- indicating assays. In some cases UV
spectroscopy
can be used, but in general chromatography is
required to separate the drug from its degradation
products and any excipients.
Rakesh Kumar Sharma 54
55. EXCIPIENT COMPATIBILITY
The successful formulation of a stable and
effective solid dosage form depends on the careful
selection of the excipients that are added to
facilitate administration, promote the consistent
release and bioavailability of the drug and protect
it from degradation.
Rakesh Kumar Sharma 55
56. Thermal analysis can be used to investigate and
predict any physicochemical interactions between
components in a formulation and can therefore be
applied to the selection of suitable chemically
compatible excipients.
Primary excipients recommended for initial
screening for tablet and capsule formulations are
shown in Table
Rakesh Kumar Sharma 56
59. Basically, The thermal properties of a physical
mixture are the sum of the individual components,
and this thermogram can be compared with those
of the drug and the excipients alone.
An interaction on DSC will show as changes in
melting point, peak shape and area and/or the
appearance of a transition.
Rakesh Kumar Sharma 59
60. CONCLUSIONS
Preformulation studies have a significant part to play
in anticipating formulation problems and identifying
logical paths in both liquid and solid dosage form
technology (Figure).
The availability of good solubility data should allow
the selection of the most appropriate salt for
development.
Rakesh Kumar Sharma 60
61. Stability studies in solution will indicate the
feasibility of parenteral or other liquid dosage
forms, and can identify methods of stabilization.
In parallel, solid-state stability by DSC, TLC and
HPLC, and in the presence of tablet and capsule
excipients, will indicate the most acceptable
vehicles for solid dosage forms.
Rakesh Kumar Sharma 61