The document discusses various aspects of pharmaceutical co-crystals including definitions, types, characterization techniques, preparation methods and applications based on a literature review. Key points include: co-crystals can improve properties like solubility, bioavailability of APIs; common preparation methods are solvent evaporation, slurry conversion and solvent drop grinding; characterization involves techniques like PXRD, DSC, FTIR; literature examples demonstrate enhanced dissolution and bioavailability of drugs like atorvastatin, meloxicam through co-crystallization.
Co-crystals for improved physicochemical properties of poorly soluble drug Sana Roohi
Role of co-crystals in enhancement of physicochemical properties like flowability, chemical stability, dissolution characteristics of poorly soluble drugs
The document discusses co-crystals, which are crystalline materials composed of an active pharmaceutical ingredient and a co-crystal former. Co-crystals can improve properties like dissolution rate and stability. They are formed through hydrogen bonding, pi-stacking, or van der Waals forces between components. Common preparation methods include solution crystallization, grinding, and antisolvent crystallization. Co-crystals are characterized using techniques like infrared spectroscopy, X-ray crystallography, and thermal analysis. Examples of co-crystallized drugs discussed include itraconazole, caffeine, and carbamazepine.
This presentation provides an overview of cyclodextrins including their types, properties, synthesis, inclusion complex formation, modifications, applications, and side effects. Cyclodextrins are formed by an enzyme acting on starch and consist of ring molecules that can form inclusion complexes by trapping guest molecules inside their cavity. This improves properties like solubility, dissolution, stability, and decreases volatility. Common types include alpha, beta, and gamma cyclodextrin which differ in size and properties. Cyclodextrin inclusion complexes have various pharmaceutical applications such as oral, parenteral, and topical drug delivery systems.
The document discusses various physical properties of drug molecules, including additive, colligative, and constitutive properties. It describes several methods for adjusting the tonicity of drug solutions, including the sodium chloride equivalent method and White-Vincent method. The document also covers topics like dipole moment, dielectric constant, refractive index, molar refraction, and the use of Abbe's refractometer.
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.
This document discusses the use of thermal analysis techniques like differential thermal analysis (DTA), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) in preformulation studies. These techniques are used to characterize properties of drug substances and excipients like polymorphism, degree of crystallinity, moisture content, and thermal stability. They provide important information on aspects like purity, solid-solid interactions, and decomposition behavior which helps optimize dosage form development. The principles and applications of DTA, DSC, and TGA are explained to analyze various thermal events in materials.
Co-crystals for improved physicochemical properties of poorly soluble drug Sana Roohi
Role of co-crystals in enhancement of physicochemical properties like flowability, chemical stability, dissolution characteristics of poorly soluble drugs
The document discusses co-crystals, which are crystalline materials composed of an active pharmaceutical ingredient and a co-crystal former. Co-crystals can improve properties like dissolution rate and stability. They are formed through hydrogen bonding, pi-stacking, or van der Waals forces between components. Common preparation methods include solution crystallization, grinding, and antisolvent crystallization. Co-crystals are characterized using techniques like infrared spectroscopy, X-ray crystallography, and thermal analysis. Examples of co-crystallized drugs discussed include itraconazole, caffeine, and carbamazepine.
This presentation provides an overview of cyclodextrins including their types, properties, synthesis, inclusion complex formation, modifications, applications, and side effects. Cyclodextrins are formed by an enzyme acting on starch and consist of ring molecules that can form inclusion complexes by trapping guest molecules inside their cavity. This improves properties like solubility, dissolution, stability, and decreases volatility. Common types include alpha, beta, and gamma cyclodextrin which differ in size and properties. Cyclodextrin inclusion complexes have various pharmaceutical applications such as oral, parenteral, and topical drug delivery systems.
The document discusses various physical properties of drug molecules, including additive, colligative, and constitutive properties. It describes several methods for adjusting the tonicity of drug solutions, including the sodium chloride equivalent method and White-Vincent method. The document also covers topics like dipole moment, dielectric constant, refractive index, molar refraction, and the use of Abbe's refractometer.
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.
This document discusses the use of thermal analysis techniques like differential thermal analysis (DTA), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) in preformulation studies. These techniques are used to characterize properties of drug substances and excipients like polymorphism, degree of crystallinity, moisture content, and thermal stability. They provide important information on aspects like purity, solid-solid interactions, and decomposition behavior which helps optimize dosage form development. The principles and applications of DTA, DSC, and TGA are explained to analyze various thermal events in materials.
State of matter and properties of matter (Part-7)(Solid-crystalline, Amorpho...Ms. Pooja Bhandare
CRYSTALLINE SOLID, Types of Crystalline solid, AMORPHOUS SOLID, Difference between crystalline solid and amorphous solid, Why does the amorphous form of drug have better bioavaibility that crystalline couterpaerts?, Polymorphism,
TYPES OF POLYMORPHISM, PROPERTY OF POLYMORPHS, Methods of preparation of Polymorphs, Methods to determine Polymorphism Characterization of Polymorphs, Pharmaceutical Application
It is a Complexaing agent.
Synonym: cavitron, cycloamyloses, cycloglucan, cyclic oligosaccharide
It is a important for increasing the solubility of poorly water soluble drugs.
Cyclodextrines are produced from starch by means of enzymatic conversion.
They are used in food, pharmaceutical, drug delivery, and chemical industries, as well as agriculture and environmental engineering.
Cyclodextrines are composed of 5 or more α-D glucopyranoside units linked 1->4, as in amylose linkage.
Cyclodextrines contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring.
CDs, with lipophilic inner cavities & hydrophilic outer surfaces, are interacting with a guest molecule to form non covalent inclusion complexes.
Today CDs are only synthesized either by fermentation or enzymatically.
Many CGTases from different microorganisms are known, cloned, sequenced, characterized and used for production of CDs.
Accelerated stability studies are conducted to increase the rate of chemical degradation or physical change of a drug product by using exaggerated storage conditions. The Arrhenius equation describes the dependence of the reaction rate constant on temperature and can be used to extrapolate accelerated stability data to long-term storage conditions. Types of accelerated stability tests include those at elevated temperatures, high intensity light, high partial pressure of oxygen, and high relative humidity. However, accelerated stability testing has limitations when degradation is caused by factors other than temperature, such as microbial contamination or diffusion, or when a product loses physical integrity at higher temperatures. International guidelines provide recommendations for conducting stress tests and evaluating stability data.
Seminar on solid state stability and shelf life by ranjeet singhRanjeet Singh
This seminar discusses the stability of solid drug substances and techniques for determining shelf life. Stability is defined as a drug substance remaining within specified limits of identity, strength, quality and purity during storage and use. Solid drugs can undergo physical transformations like polymorphic transitions, formation of hydrates or amorphous forms. Analytical techniques are used to identify these changes. Shelf life studies involve real time testing at recommended storage conditions or accelerated testing at elevated temperatures to estimate shelf life under normal conditions. Factors like temperature, moisture, pH and light exposure can influence drug degradation and must be considered.
This document discusses co-crystals, which are crystalline materials composed of two or more components in the same crystal lattice. It outlines several advantages of co-crystals such as increased stability and solubility compared to amorphous forms. Common preparation methods include solution methods, grinding, and antisolvent techniques. Key characterization techniques are X-ray powder diffraction, infrared spectroscopy, and solubility analysis. Several marketed drug formulations utilizing co-crystals are also mentioned.
Principle and application of dsc,dta,ftir and x ray diffractionBhavesh Maktarpara
The document discusses various thermal analysis techniques used in preformulation including DSC, DTA, FTIR, and X-ray diffraction. It describes the principles of each technique and provides examples of their applications in determining impurities, polymorphism, hydrates/solvates, crystallinity, drug-excipient compatibility, and more. These techniques are valuable tools for characterization during preformulation studies.
This document provides an overview of solubility and dissolution. It defines key terms like solubility, dissolution, and saturation solubility. It discusses factors that affect solubility like temperature, particle size, and polarity. It also describes different techniques to improve solubility including use of co-solvents, surfactants, and complexation. Surfactants can improve solubility through micelle formation. The document is intended as an introduction to solubility and techniques to enhance solubility of poorly soluble drugs.
This document discusses pharmaceutical solid forms, including polymorphs, hydrates, solvates, salts, co-crystals, and amorphous forms. It covers the impact of solid form on properties like solubility, stability, and processing. The document also discusses solid form screening, characterization, and selection methods to develop solid forms that balance solubility, stability, and manufacturability for drug products. Thermodynamics concepts like Gibbs free energy, enthalpy, and entropy are applied to explain relative stability of different solid forms.
Gel is a soft solid which contains both solid & liquid components where the solid component (gelator) is present as a mesh/network of aggregates, which immobilizes the liquid component
Polymorphism refers to a solid material existing in two or more crystalline forms with different arrangements in the crystal lattice. Over 50% of active pharmaceutical ingredients have more than one polymorphic form, which can exhibit different properties like solubility, dissolution rate, and stability. Methods to identify polymorphs include x-ray diffraction, differential scanning calorimetry, and thermal microscopy. The choice of polymorph is important for drug formulations, as the metastable form may have better bioavailability but convert to the stable form, impacting suspension stability or drug absorption. Case studies show certain polymorphs can be medically inactive or cause production issues if they convert dominant forms.
This document discusses mechanisms of drug dissolution from solid oral dosage forms. It begins with an introduction on the importance of dissolution testing. It then covers several theories of dissolution mechanisms including diffusion layer theory, reaction limited models, and the Carstensen scheme. Mathematical models of drug release kinetics are also discussed, including zero-order, first-order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell models. The document provides details on each model and their applications and limitations in describing drug dissolution and release profiles from different drug delivery systems.
1. The document discusses different types of complexes that can form between molecules, including metal ion complexes, organic molecular complexes, and inclusion complexes.
2. Metal ion complexes involve donation of electron pairs from ligands to a central metal ion. Important types include inorganic complexes containing ligands like ammonia, and chelate complexes where a ligand donates multiple electron pairs.
3. Organic molecular complexes are weaker and involve polarization of molecules and charge transfer rather than covalent bonding. Examples discussed include complexes of drugs containing N-C=S moieties that can complex with iodine.
This document describes buffer solutions and how to calculate their pH and buffer capacity. Buffer solutions contain a weak acid or base and its salt, and resist changes in pH when acids or bases are added. The Henderson-Hasselbalch equation relates the pH of a buffer to the ratio of concentrations of its salt and acid or base components. Buffer capacity is the ability to resist pH change upon addition of acids or bases, and is greatest when the salt and acid are present in equimolar amounts. Common buffer systems used in pharmaceuticals are also mentioned.
This document discusses solubility of drugs and factors that influence drug solubility. It begins by listing topics that will be covered, including solubility expressions, mechanisms of solute-solvent interactions, ideal solubility parameters, solvation and association, quantitative approaches to factors influencing drug solubility, and principles of diffusion in biological systems. It then lists learning objectives which are to define solubility terms, understand solubility of gases, solids and liquids in liquids, and concepts such as Raoult's law, real solutions, phase diagrams and critical solution temperature. The document then discusses these topics in more detail over several pages.
Surface and Interfacial tension [Part-3(a)](Measurement of Surface and Inter...Ms. Pooja Bhandare
MEASUREMENT OF SURFACE AND INTERFACIAL TENSION
Capillary Rise Method, Drop Count and Weight Method.
Wilhelmy Plate Methods ,The DuNouy Ring Method.
Capillary Rise Method: Upward force due to surface tension: Drop count and Weight method Downward Force: Drop weight method: Drop count method
This document discusses the co-crystal technique for enhancing the solubility of poorly water soluble drugs. It introduces co-crystals as crystalline materials comprised of an active pharmaceutical ingredient and one or more co-crystal formers. Co-crystals can improve solubility and bioavailability through interactions like hydrogen bonding and pi-stacking. The document outlines various methods for preparing co-crystals, including solution methods, grinding, and supercritical fluid technology. It also discusses selecting appropriate co-formers, solvents, and evaluation methods like powder X-ray diffraction and solubility analysis. Several marketed drug products incorporating co-crystal technology are presented as examples.
drug execipent compatibilty studies is of prime importance for the better formulation of the new drug and also for reducing cost by verfication of the data at the earlier atage.
this presentation will give the brief explanation of the goal, importance, dteps involve to studi the drug execient compatibility studies with different examples suitable accordiingly.
Heterocyclic chemistry - Fused ring systemsNaresh Babu
The document discusses the structures and properties of quinoline, isoquinoline, and indole. Quinoline and isoquinoline are fused aromatic ring systems consisting of benzene fused to pyridine with the nitrogen at different positions. Indole is a fused aromatic ring system consisting of benzene fused to pyrrole. The structures are described including hybridization and delocalized pi orbitals. Common preparation methods are outlined such as Skraup synthesis for quinoline and Bischler-Napieralski synthesis for isoquinoline. Key chemical reactions including electrophilic substitution, reduction, and reactions with acids and bases are also summarized.
1. The document discusses cocrystals for solubility enhancement of APIs. Cocrystals are crystalline materials made of an API and coformer in a stoichiometric ratio.
2. Several methods are described for preparing cocrystals including solvent evaporation, slurry technique, solid state grinding, and spray drying. Characterization techniques like XRD, DSC, and IR are used to analyze the cocrystals.
3. Examples demonstrate how cocrystallization can increase solubility and bioavailability of APIs like sildenafil, danazol, and aceclofenac. The "spring and parachute" concept is discussed for maintaining supersaturation of drugs to enhance absorption.
1. The document discusses cocrystals for solubility enhancement of APIs. Cocrystals are crystalline materials made of an API and coformer in a stoichiometric ratio.
2. Several methods are described for preparing cocrystals including solvent evaporation, slurry technique, solid state grinding, and spray drying. Characterization techniques like XRD, DSC, and IR are used to analyze the cocrystals.
3. Examples demonstrate how cocrystallization can increase solubility and bioavailability of APIs like sildenafil, danazol, and aceclofenac. The "spring and parachute" concept is discussed for maintaining supersaturation of drugs to enhance absorption.
State of matter and properties of matter (Part-7)(Solid-crystalline, Amorpho...Ms. Pooja Bhandare
CRYSTALLINE SOLID, Types of Crystalline solid, AMORPHOUS SOLID, Difference between crystalline solid and amorphous solid, Why does the amorphous form of drug have better bioavaibility that crystalline couterpaerts?, Polymorphism,
TYPES OF POLYMORPHISM, PROPERTY OF POLYMORPHS, Methods of preparation of Polymorphs, Methods to determine Polymorphism Characterization of Polymorphs, Pharmaceutical Application
It is a Complexaing agent.
Synonym: cavitron, cycloamyloses, cycloglucan, cyclic oligosaccharide
It is a important for increasing the solubility of poorly water soluble drugs.
Cyclodextrines are produced from starch by means of enzymatic conversion.
They are used in food, pharmaceutical, drug delivery, and chemical industries, as well as agriculture and environmental engineering.
Cyclodextrines are composed of 5 or more α-D glucopyranoside units linked 1->4, as in amylose linkage.
Cyclodextrines contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring.
CDs, with lipophilic inner cavities & hydrophilic outer surfaces, are interacting with a guest molecule to form non covalent inclusion complexes.
Today CDs are only synthesized either by fermentation or enzymatically.
Many CGTases from different microorganisms are known, cloned, sequenced, characterized and used for production of CDs.
Accelerated stability studies are conducted to increase the rate of chemical degradation or physical change of a drug product by using exaggerated storage conditions. The Arrhenius equation describes the dependence of the reaction rate constant on temperature and can be used to extrapolate accelerated stability data to long-term storage conditions. Types of accelerated stability tests include those at elevated temperatures, high intensity light, high partial pressure of oxygen, and high relative humidity. However, accelerated stability testing has limitations when degradation is caused by factors other than temperature, such as microbial contamination or diffusion, or when a product loses physical integrity at higher temperatures. International guidelines provide recommendations for conducting stress tests and evaluating stability data.
Seminar on solid state stability and shelf life by ranjeet singhRanjeet Singh
This seminar discusses the stability of solid drug substances and techniques for determining shelf life. Stability is defined as a drug substance remaining within specified limits of identity, strength, quality and purity during storage and use. Solid drugs can undergo physical transformations like polymorphic transitions, formation of hydrates or amorphous forms. Analytical techniques are used to identify these changes. Shelf life studies involve real time testing at recommended storage conditions or accelerated testing at elevated temperatures to estimate shelf life under normal conditions. Factors like temperature, moisture, pH and light exposure can influence drug degradation and must be considered.
This document discusses co-crystals, which are crystalline materials composed of two or more components in the same crystal lattice. It outlines several advantages of co-crystals such as increased stability and solubility compared to amorphous forms. Common preparation methods include solution methods, grinding, and antisolvent techniques. Key characterization techniques are X-ray powder diffraction, infrared spectroscopy, and solubility analysis. Several marketed drug formulations utilizing co-crystals are also mentioned.
Principle and application of dsc,dta,ftir and x ray diffractionBhavesh Maktarpara
The document discusses various thermal analysis techniques used in preformulation including DSC, DTA, FTIR, and X-ray diffraction. It describes the principles of each technique and provides examples of their applications in determining impurities, polymorphism, hydrates/solvates, crystallinity, drug-excipient compatibility, and more. These techniques are valuable tools for characterization during preformulation studies.
This document provides an overview of solubility and dissolution. It defines key terms like solubility, dissolution, and saturation solubility. It discusses factors that affect solubility like temperature, particle size, and polarity. It also describes different techniques to improve solubility including use of co-solvents, surfactants, and complexation. Surfactants can improve solubility through micelle formation. The document is intended as an introduction to solubility and techniques to enhance solubility of poorly soluble drugs.
This document discusses pharmaceutical solid forms, including polymorphs, hydrates, solvates, salts, co-crystals, and amorphous forms. It covers the impact of solid form on properties like solubility, stability, and processing. The document also discusses solid form screening, characterization, and selection methods to develop solid forms that balance solubility, stability, and manufacturability for drug products. Thermodynamics concepts like Gibbs free energy, enthalpy, and entropy are applied to explain relative stability of different solid forms.
Gel is a soft solid which contains both solid & liquid components where the solid component (gelator) is present as a mesh/network of aggregates, which immobilizes the liquid component
Polymorphism refers to a solid material existing in two or more crystalline forms with different arrangements in the crystal lattice. Over 50% of active pharmaceutical ingredients have more than one polymorphic form, which can exhibit different properties like solubility, dissolution rate, and stability. Methods to identify polymorphs include x-ray diffraction, differential scanning calorimetry, and thermal microscopy. The choice of polymorph is important for drug formulations, as the metastable form may have better bioavailability but convert to the stable form, impacting suspension stability or drug absorption. Case studies show certain polymorphs can be medically inactive or cause production issues if they convert dominant forms.
This document discusses mechanisms of drug dissolution from solid oral dosage forms. It begins with an introduction on the importance of dissolution testing. It then covers several theories of dissolution mechanisms including diffusion layer theory, reaction limited models, and the Carstensen scheme. Mathematical models of drug release kinetics are also discussed, including zero-order, first-order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell models. The document provides details on each model and their applications and limitations in describing drug dissolution and release profiles from different drug delivery systems.
1. The document discusses different types of complexes that can form between molecules, including metal ion complexes, organic molecular complexes, and inclusion complexes.
2. Metal ion complexes involve donation of electron pairs from ligands to a central metal ion. Important types include inorganic complexes containing ligands like ammonia, and chelate complexes where a ligand donates multiple electron pairs.
3. Organic molecular complexes are weaker and involve polarization of molecules and charge transfer rather than covalent bonding. Examples discussed include complexes of drugs containing N-C=S moieties that can complex with iodine.
This document describes buffer solutions and how to calculate their pH and buffer capacity. Buffer solutions contain a weak acid or base and its salt, and resist changes in pH when acids or bases are added. The Henderson-Hasselbalch equation relates the pH of a buffer to the ratio of concentrations of its salt and acid or base components. Buffer capacity is the ability to resist pH change upon addition of acids or bases, and is greatest when the salt and acid are present in equimolar amounts. Common buffer systems used in pharmaceuticals are also mentioned.
This document discusses solubility of drugs and factors that influence drug solubility. It begins by listing topics that will be covered, including solubility expressions, mechanisms of solute-solvent interactions, ideal solubility parameters, solvation and association, quantitative approaches to factors influencing drug solubility, and principles of diffusion in biological systems. It then lists learning objectives which are to define solubility terms, understand solubility of gases, solids and liquids in liquids, and concepts such as Raoult's law, real solutions, phase diagrams and critical solution temperature. The document then discusses these topics in more detail over several pages.
Surface and Interfacial tension [Part-3(a)](Measurement of Surface and Inter...Ms. Pooja Bhandare
MEASUREMENT OF SURFACE AND INTERFACIAL TENSION
Capillary Rise Method, Drop Count and Weight Method.
Wilhelmy Plate Methods ,The DuNouy Ring Method.
Capillary Rise Method: Upward force due to surface tension: Drop count and Weight method Downward Force: Drop weight method: Drop count method
This document discusses the co-crystal technique for enhancing the solubility of poorly water soluble drugs. It introduces co-crystals as crystalline materials comprised of an active pharmaceutical ingredient and one or more co-crystal formers. Co-crystals can improve solubility and bioavailability through interactions like hydrogen bonding and pi-stacking. The document outlines various methods for preparing co-crystals, including solution methods, grinding, and supercritical fluid technology. It also discusses selecting appropriate co-formers, solvents, and evaluation methods like powder X-ray diffraction and solubility analysis. Several marketed drug products incorporating co-crystal technology are presented as examples.
drug execipent compatibilty studies is of prime importance for the better formulation of the new drug and also for reducing cost by verfication of the data at the earlier atage.
this presentation will give the brief explanation of the goal, importance, dteps involve to studi the drug execient compatibility studies with different examples suitable accordiingly.
Heterocyclic chemistry - Fused ring systemsNaresh Babu
The document discusses the structures and properties of quinoline, isoquinoline, and indole. Quinoline and isoquinoline are fused aromatic ring systems consisting of benzene fused to pyridine with the nitrogen at different positions. Indole is a fused aromatic ring system consisting of benzene fused to pyrrole. The structures are described including hybridization and delocalized pi orbitals. Common preparation methods are outlined such as Skraup synthesis for quinoline and Bischler-Napieralski synthesis for isoquinoline. Key chemical reactions including electrophilic substitution, reduction, and reactions with acids and bases are also summarized.
1. The document discusses cocrystals for solubility enhancement of APIs. Cocrystals are crystalline materials made of an API and coformer in a stoichiometric ratio.
2. Several methods are described for preparing cocrystals including solvent evaporation, slurry technique, solid state grinding, and spray drying. Characterization techniques like XRD, DSC, and IR are used to analyze the cocrystals.
3. Examples demonstrate how cocrystallization can increase solubility and bioavailability of APIs like sildenafil, danazol, and aceclofenac. The "spring and parachute" concept is discussed for maintaining supersaturation of drugs to enhance absorption.
1. The document discusses cocrystals for solubility enhancement of APIs. Cocrystals are crystalline materials made of an API and coformer in a stoichiometric ratio.
2. Several methods are described for preparing cocrystals including solvent evaporation, slurry technique, solid state grinding, and spray drying. Characterization techniques like XRD, DSC, and IR are used to analyze the cocrystals.
3. Examples demonstrate how cocrystallization can increase solubility and bioavailability of APIs like sildenafil, danazol, and aceclofenac. The "spring and parachute" concept is discussed for maintaining supersaturation of drugs to enhance absorption.
PREFORMULATION STUDY IN DESIGNING OF TABLET DOSAGES FORM.pptxSWASTIKPATNAIK1
Preformulation studies are important for determining the physicochemical properties of new drug substances before developing dosage forms. This document outlines preformulation studies conducted for omeprazole magnesium and carbamazepine to aid in the development of enteric coated tablets and buccal mucoadhesive tablets, respectively. Key tests included solubility analysis, stability analysis, particle size characterization, and in vitro drug release studies. The results of these preformulation studies provided guidance on suitable excipients and helped establish formulation designs and processing parameters to achieve the desired drug delivery profiles.
The document discusses preformulation studies for solids. The objectives are to develop a stable, safe and effective dosage form with maximum bioavailability. Preformulation testing characterizes the physical, chemical and other properties of a new drug to aid in dosage form development. Studies include analyzing the drug's crystallinity, polymorphism, particle size, solubility, stability and compatibility with excipients. Analytical techniques used include microscopy, spectroscopy, chromatography and thermal analysis to understand the drug's properties and develop an optimal dosage form.
This document discusses various techniques to enhance the solubility of drugs for improved bioavailability in oral dosage forms. It outlines 10 main approaches: 1) reducing particle size, 2) use of surfactants for micellar solubilization, 3) complexation, 4) chemical modification, 5) hydrotropy, 6) various amorphous drug forms, 7) modifying pH, 8) use of solvates and hydrates, 9) changing dielectric constant. Specific techniques are described under each approach, such as nanoparticle formation through micro-milling or use of cyclodextrins for complexation. The effects of factors like pH, ionic strength, and alcohol concentration on drug solubility and dissociation constants are
Stability Indicating HPLC Method Development A Reviewijtsrd
High performance liquid chromatography is most powerful tools in analytical chemistry which assessing drug product stability. It is most accurate method for determining the qualitative and quantitative analysis of drug product. Forced degradation plays an important role in development of stability indicating analytical methodology. Stability indicating HPLC methods are used to separate various drug related impurities that are formed during the synthesis or manufacture of drug product. This article discusses the strategies and issues regarding the development of stability indicating HPLC system for drug substance. Forced degradation studies establish degradation pathways of drug substances and drug products. Forced degradation elucidate the possible degradation pathway of the drug substance or the active pharmaceutical ingredient in the drug product. At every stage of drug development practical recommendations are provided which will help to avoid failure. Rushikesh S Mulay | Rishikesh S Bachhav "Stability Indicating HPLC Method Development - A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-5 | Issue-6 , October 2021, URL: https://www.ijtsrd.com/papers/ijtsrd46342.pdf Paper URL : https://www.ijtsrd.com/pharmacy/analytical-chemistry/46342/stability-indicating-hplc-method-development--a-review/rushikesh-s-mulay
This document discusses preformulation for new drug development. A change in formulation, dosage, route of administration, or dosage form of an existing drug causes it to be considered "new" and requires safety and efficacy evaluation. Preformulation aims to optimize a drug's physical and chemical properties for a stable, effective dosage form. It involves characterizing the drug molecule and developing the dosage form. Some goals of preformulation include establishing the drug's physicochemical parameters, kinetic profile, physical characteristics, and compatibility with excipients. Polymorphism, or the ability of a drug to exist in different crystal forms, is also evaluated as it can impact properties like solubility, dissolution rate, and bioavailability.
Pre-formulation studies involve evaluating the physical and chemical properties of an active pharmaceutical ingredient prior to formulation development. This helps understand the drug's behavior and identify suitable excipients and dosage forms. Key aspects of pre-formulation studies include evaluating solubility, stability, dissolution rate, and compatibility with excipients. Techniques like DSC, FTIR, XRD are used to analyze properties like crystallinity, polymorphism and for compatibility testing. Together, pre-formulation studies provide critical data to inform the rational development of a stable and effective dosage form.
mehods to enhance the solubility of poorly soluble drugsPraveenHalagali
Mr. Praveen Halagali presented on different techniques to enhance drug solubility to Dr. D.V. Gowda. The presentation covered the importance of solubility for drug bioavailability and listed various physical, chemical, and technological methods to improve solubility. These included reducing particle size, modifying crystal forms, complexation, and use of surfactants, cosolvents, and nanotechnology approaches like nanocrystals and nanomorphs. The mechanisms and specific techniques involved in each method were described in detail.
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.
The document discusses niosomes, which are nano-sized vesicles created from non-ionic surfactants, as a drug delivery system. Niosomes can encapsulate drugs and release them in a controlled manner. The document outlines the structure and properties of niosomes. It also discusses how naringin, a natural flavonoid, was encapsulated in niosomes and tested for encapsulation efficiency, particle size, drug release kinetics and stability. The naringin-loaded niosomes showed sustained release over 24 hours and have potential as a drug delivery system for transdermal administration.
This document discusses preformulation, which involves characterizing the physical and chemical properties of a new drug substance to develop a stable, safe, and effective dosage form. The goals are to establish properties like solubility, stability, and kinetics. Key aspects covered include solubility analysis, partition coefficient, chemical stability studies like hydrolysis and oxidation, polymorphism, and particle size analysis. Understanding these characteristics is essential for rational dosage form development and selection.
Pharmacosomes are colloidal dispersions of drugs that are covalently bound to lipids. They can exist as ultrafine vesicular, micellar, or hexagonal aggregates depending on the chemical structure of the drug-lipid complex. Pharmacosomes have advantages over other drug delivery systems like liposomes in that the drug is covalently bound so there is no leaching and release is controlled. They can be prepared using methods like hand shaking, ether injection, lyophilization, or solvent evaporation. Pharmacosomes are evaluated for complex formation, morphology, solubility, drug-lipid compatibility, drug entrapment, and in vitro drug release.
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 provides an overview of preformulation studies. It discusses the importance of characterizing the physical and chemical properties of new drug molecules during preformulation to aid in the development of stable dosage forms. Some of the key areas covered include drug-excipient compatibility studies, stability kinetics testing, and determining properties like solubility, partition coefficient, and polymorphism that can help dictate the suitable dosage form. The goal of preformulation is to gather necessary data to rationally develop safe and efficacious dosage forms.
The document summarizes the formulation and evaluation of diclofenac sodium and thiocolchicoside as a topical gel. It describes preparing 6 formulations of gel using different polymers and permeation enhancers. The formulations were characterized for physical properties, pH, drug content, viscosity, spreadability, extrudability and stability. In vitro drug permeation and skin irritation studies were also performed to select the best formulation. Preformulation studies including solubility, melting point, UV, FTIR and DSC were done on the drugs and excipients to ensure compatibility. The results of various evaluation tests are presented and the best gel formulation is selected based on desired properties.
The document discusses various physicochemical properties that can affect bioequivalence studies, including crystal morphology, polymorphism, solvates, hydrates, complexation, surface activity, hygroscopicity, particle size, solubility and dissolution. It explains how these properties can influence parameters like raw material characteristics, reproducibility, performance of the dosage form, absorption rate and extent. Factors like ionization, partitioning, distribution coefficient, chemical structure and salt forms are also covered in relation to their effects on solubility, dissolution and absorption of drug substances and products.
SOLID DISPERSION
Definition: The technology is the science of dispersing one or more active ingredients in an inert matrix in the solid stage.
Need of solid dispersion:
Increases Oral bioavailability of a drug
Increased dissolution rate.
Enhanced release of drugs from ointment.
Improved the solubility & stability.
The concept of solid dispersion was originally proposed by Sekiguchi & obi.
Increasing the dissolution, absorption & therapeutic efficacy of drugs in dosage forms.
Increasing solubility in water.
Improving the oral absorption and bioavailability of BCS Class II drugs.
DESIGN AND ASSESSMENT OF COLON SPECIFIC DRUG DELIVERY OF CELECOXIB USING PU...Lakshmi
The document summarizes the design and assessment of a colon-specific drug delivery system for celecoxib using pulsincap technique. Celecoxib microcrystals were prepared using a rapid solvent change method and evaluated. The microcrystals were then used to prepare pulsincaps containing hydrogel plugs to provide a lag time before drug release. In vitro drug release studies were conducted on the pulsincaps to assess their ability to deliver celecoxib in a pulsatile manner to the colon. The aim was to improve solubility, target delivery to the colon, and minimize dosing frequency for the treatment of rheumatoid arthritis.
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2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
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4. 4
• Physicochemical properties of API are key parameters in developing acceptable
dosage form in determining the efficacy, activity of a drug.
• Co-crystals formation has emerged as a viable strategy towards improving the
solubility and bioavailability of poorly soluble drugs.
• Desiraju defined crystal engineering as ‘the understanding of intermolecular
interactions in the context of crystal packing and in the utilization of such
understanding in the design of new solids with desired physical and chemical
properties’.
5. • Aakeroy and Salmon defined co-crystals as structurally homogeneous crystalline
materials containing two or more components present in definite stoichiometric
amounts.
• “A stoichiometric multi-component system connected by non-covalent
interactions where all the components present are solid under ambient
conditions”.
• The FDA defines co-crystals as ‘solids that are crystalline materials composed of
two or more molecules in the same crystal lattice’.
• API-excipient molecular complex
5
7. 7
• It is assembly of 2 or more different molecules with superior physical properties
than individual component.
• Intermolecular interactions involved include van der waals contacts, stacking
interactions and the hydrogen bonding.
Figure 1-2: Adenine co-crystals
8. 8
Types of co-crystals
Anhydrates Hydrates (solvates)
Hydrates of co-
crystals of salts
Anhydrates of co-
crystals of salts
Figure 1-3: Types of co-crystals
9. 9
• The coformer properties and interactions provide strategies to control co-crystal
solubility.
• Synthons are formed by the gathering of two molecules through molecular
functionalities that interact with each other in a predictable fashion by non-covalent
interactions.
• Intermolecular hydrogen bonding can be assessed using Cambridge Structural
Database, Hansen solubility parameters (HSPs), supramolecular synthon approach.
Figure 1-4: Common hydrogen bonded synthons used in crystal engineering
11. 11
Solvent Evaporation: It involves super saturation of solution by evaporation, cooling
and addition of solubility changing solvent.
Eg: Fluoxetine hydrochloride-succinic acid, fumaric acid.
Slurry Crystallization: Equimolar proportion of the two coformers are dissolved in
small amount of different solvents at ambient temperature, evaporated and the solvent
is decanted and the material is dried.
Eg: Aspirin-4, 4-Dipyridil.
Solvent drop grinding: Grinding of two materials together with incorporation of small
quantity of solvent. Enhances the rate of co crystal formation, increased yield, control
polymorph production, better product crystallinity.
Eg: Caffeine-glutaric acid co-crystal.
12. 12
• Neat grinding: Mechanical grinding using ball mill, vibratory mill or by manual
grinding using motor and pestle. Polymorphic transition may occur.
Eg: Sulfadimidine –salicylic acid co-crystal.
• Supercritical fluid technology allows a single-step generation of particles. The
properties of different super critical fluids assist in generation of pure and dried co-
crystals.
• Antisolvent addition: It involves precipitation or recrystalization of the two co-
crystal former. Solvents consist of buffers and organic solvents.
Eg: Aceclofenac-chitosan (distilled water/sodium citrate).
• Hot melt extrusion: It involves highly efficient mixing and improved surface
contacts, co-crystals are prepared without use of solvent. The selection of this
method primarily depends on thermodynamic stability of compound.
Eg: Carbamazepine-nicotinamide co-crystals.
13. 13
• Pharmaceutical co-crystallization can be employed to all APIs and drugs lacking
ionizable functional groups (phenol) and compounds with sensitive group to
treatment of acids and bases.
• Enhances solubility and bioavailability of poorly soluble drugs.
• Improve the physicochemical properties of a drug without affecting its intrinsic
structure .
• Enhance other essential properties of the APIs such as flowability, chemical
stability, compressability and hygroscopicity.
• The existence of numerous potential counter molecules (food additives,
preservatives, pharmaceutical excipients) for co-crystal synthesis.
• Address intellectual property (IP) issues by extending the life cycles of old API.
14. 14
• In solid state grinding method, optimum temperature range should be known
• It is difficult to identify the structure.
• Phase separation of co-crystals into individual component on storage.
• Phase change may occur during formulation development of API.
16. • Supersaturation is used as a strategy to improve solubility and dissolution rate of
poorly soluble drugs.
• Two critical steps need to be maintained:
1. Generation of the metastable supersaturated state
2. Maintenance of the above state
16
17. 17
Figure 1-7: The spring and parachute concept to achieve high apparent
solubility for insoluble drugs
20. 20
• Pharmaceutical co-crystals of existing APIs exhibiting clinical advantages can be
developed as new drugs.
• Pharmaceuticals: The co-crystal formed from the chemotheraphy agent, tegafure
showed solubility much higher than that in pure crystalline phase.
• Cosmetics: co-crystals of 3-iodopropynyl butylcarbamate, an antifungal agent was
reported to have greater solubility in water, heat stability and better processability
properties.
• Agrochemicals: co-crystals were also used to raise the melting point of an
imidacloprid insecticide using oxalic acid with better shelf stability.
• Chromophores: co-crystals of titanyl fluorothalocyanine with titanyl fluorocyanine
have a novel spectrum with improved electrophotographic sensitivity.
• Alter electrical properties and shown to have potential as organic semi-conductors.
22. 22
Title Authors
Year &
Journal
Conclusion
Synthesis of a
glibenclamide
cocrystal: full
spectroscopic and
thermal
characterization
Silva Filho SF
et al.
Journal of
Pharmaceutical
Sciences, 2018
Synthesised co-crystal of glibenclamide
using tromethamine (TRIS) by slow
solvent evaporation co-crystallization.
The co-crystal obtained was
characterized by XRD, DSC, Raman,
mid infrared and near-infrared
spectroscopy. The results showed the
formation of a co-crystal between API
and conformer with the synthons
corresponding to hydrogen bonding
between hydrogen in amines of
tromethamine and carbonyl and sulfonyl
groups in glibenclamide.
23. 23
Title Authors
Year &
Journal
Conclusion
Solubility
enhancement of
lornoxicam by
crystal
engineering
D. D.
Gadade
et al.
Indian Journal
of
Pharmaceutical
Sciences,
March 2017
Co-crystals of lornoxicam were prepared by
neat grinding method with 19 different
coformers. The prepared co-crystals were
characterized by DSC, FTIR, XRD.
Maximum solubility and dissolution rate
were observed with co-crystal prepared
using saccharin sodium. Percent cumulative
drug release with marketed tablets
(Lofecam, Sun Pharma) was found to be
47.63±0.51% and 57.93±1.66% in distilled
water and phosphate buffer pH 7.4
respectively at the end of 60 min, while that
with optimized batch was 86.14±1.33% and
93.01±0.77% indicating improved
dissolution of lornoxicam by co-
crystallization
24. Title Authors
Year &
Journal
Conclusion
Enhancement of
solubility and
dissolution rate of
atorvastatin
calcium by co-
crystallization
Wicaksono
et al.
Tropical
Journal of
Pharmaceutical
Research, 2017
Co-crystallization of atorvastatin calcium
(AC) with isonicotinamide (INA) was
carried out by slow solvent evaporation
method using methanol. The solid obtained
was characterized by PXRD, DSC, FTIR,
SEM, and then further evaluated for
solubility and dissolution. The solubility of
ACINA co-crystal in distilled water (270.7
mg/L) was found to be significantly higher
than that of pure atorvastatin calcium
(140.9 mg/L). The dissolution rate of
ACINA co-crystal showed 2 - 3 times faster
drug release when compared to pure AC.
Formulation and
evaluation of
clarithromycin co-
crystals tablets
dosage forms to
enhance the
bioavailability
Pinki
Rajbhar et al.
The Pharma
Innovation
Journal, 2016
Clarithromycin co-crystals tablets were
prepared (solvent evaporation) using urea
co-crystals to improve the bioavailability.
Wet granulation method was attempted for
formulation of conventional tablets of
clarithromycin. It showed improved
solubility characteristics and in-vitro drug
release profile as compared to marketed
tablet (79.86%).
24
25. Title Authors
Year &
Journal
Conclusion
Three
pharmaceutical
co-crystals of
adefovir:
synthesis,
structures and
dissolution study
Xiaoming
Zhang et
al.
Journal of
Molecular
Structure, 2015
Three novel co-crystals of adefovir with PABA(1),
3,5-dihydroxybenzoic acid(2) and 2,6-
pyridinedicarboxlic acid(3). PXRD demonstrate
that co-crystal 1 and 2 form a strong hydrogen-
bond through the phosphoric acids of API with
water and carboxylic acids of CCF respectively.
co-crystal 3 is formed in which the phosphoric acid
groups of API are also held by the carboxylic acid
groups of CCF. The overall dissolution behavior
demonstrated that a complete release of co-crystal
3 was observed in 4 h, comparing 96.8%, 92.5%,
94.1% of co-crystal 1, 2 and API respectively
Solubility
enhancement of
nevirapine by
cocrystallisation
technique
Yogesh K.
Nalte et al.
Journal of
Pharmacy
Research,
2015
The co-crystals were prepared by neat grinding
method using maleic acid. Prepared co-crystals
were characterized by PXRD, DSC, FTIR.
Moreover they were studied for melting point
determination, flow property studies and
dissolution studies (0.1 N HCl, phosphate buffer
6.8). All the performed study revealed formation of
co-crystals, improvement in micromeritic
properties, dissolution. Drug solubility of
nevirapine was improved by 106 folds in 0.1N HCl
25
26. 26
Title Authors
Year &
Journal
Conclusion
Utilization of
co-
crystallization
for solubility
enhancement of
a poorly soluble
antiretroviral
drug – ritonavir
Londhe et
al.
International
Journal of
Pharmacy and
Pharmaceutical
Sciences, 2014
Prepared co-crystals of ritonavir with different
co-formers succinic acid (SUC), adipic acid
(ADP), nicotinamide (NIC) and D-alanine (ALA)
in ratio of 1:5 (RTN : Co-former) using solvent
grinding method and methanol as a co-solvent.
The co-crystals characterized by melting point,
FTIR, DSC, XRD and solubility studies. Co-
crystals of drug with SUC, ALA and ADP
showed 6 folds increase in solubility and the co-
crystals of RTNSUC and RTNADP showed two
times faster drug release at initial time points as
compared to RTN alone but at the end of 1 hr,
only 15% increase in drug release was found.
27. Title Authors
Year &
Journal
Conclusion
Evaluation of
performance of
co-crystals of
mefloquine
hydrochloride in
tablet dosage
form
A. S. Shete et
al.
Drug
Development
and Industrial
Pharmacy, 2013
Co-crystals of MFL with different ratio of co-
crystal formers (benzoic acid, citric acid,
oxalic acid, salicylic acid, succinic acid) were
prepared by solution co-crystalliztion using
ethanol as a solvent and these co-crystals were
incorporated in tablet dosage form and
evaluated. Succinic acid co-crystal showed
superior dissolution in both the media (SGF,
SIF) and in both co-crystal form and tablet
form. Salicylic acid showed highest
dissolution at t15 and t45 in SGF i.e., 67.8%,
84.89% respectively as compared to that of
pure MFL tablet 39.4%, 58.76% respectively.
Novel approach
of pharmaceutical
co-crystals for
poorly soluble
drugs
Tejo
Vidyulata K.
et al.
International
Journal of
Pharmaceutical
Development &
Technology,
2012
Novel co-crystal of curcumin with methyl
paraben was obtained by liquid assisted
grinding method (1:1) and was evaluated for
anti-inflammatory activity. Low doses of pure
curcumin gave less inhibitory effect of 4.65%,
whereas prepared co-crystals showed
significant inhibition effect of 66.67%.
27
28. 28
Title Authors
Year &
Journal
Conclusion
Coformer selection
in pharmaceutical
cocrystal
development: a
case study of a
meloxicam aspirin
cocrystal that
exhibits enhanced
solubility and
pharmacokinetics
Cheney et al.
Journal of
Pharmaceutical
Sciences, 2011
Targeted and prepared a co-crystal of
meloxicam and aspirin by solution, slurry, and
solvent drop grinding methods. In pH 7.4
phosphate buffer solution at 37 °C, the
solubility of meloxicam was found to be 0.005
mg/mL, whereas that of co-crystal was 0.22
mg/mL. Oral administration of co-crystal
exhibited an oral bioavailability of 69%
compared with 16% for meloxicam. Thus,
enabled an approximately 12-fold decrease in
the time required to reach a concentration of
0.51 µg/mL in rats compared with pure
meloxicam at an equivalent dose.
Improved
pharmacokinetics
of amg 517
through
co-crystallization
part 1: comparison
of two acids with
corresponding
amide co-crystals
Stanton et al.
Journal of
pharmaceutical
sciences,
2010
Studied the dissolution and pharmacokinetics
(PK) of AMG 517 co-crystals with cinnamic
acid and benzoic acid cinnamamide and
benzamide. The four co-crystals were found to
have faster intrinsic and powder dissolution
rates in FaSIF than the free base. This
correlated with a 2.4- to 7.1-fold increase in
the area under the concentration–time curve in
rat PK investigations.
29. 29
• Provided information regarding different GRAS listed coformers used for co-
crystal preparation.
• Based on the literature review it was concluded that Solvent evaporation, slurry
conversion and solvent drop grinding method are widely used for co-crystals
preparation. Out of this solvent drop grinding method was selected for co-crystal
preparation.
• An insight of literature review, furnished a glimpse of different analytical
techniques employed for characterization of co-crystals such as FTIR, DSC,
PXRD.
30. 30
Aim:- The present study envisaged to prepare and evaluate co-crystals of BCS class II
drug.
Objectives:-
Select suitable drug candidate and coformers for altering the physicochemical
properties.
Prepare co-crystals with various coformers.
Characterize the co-crystals by using different techniques like melting point,
FTIR, DSC, PXRD, particle size.
Study the physicochemical properties of prepared co-crystals.
Perform in vitro dissolution studies with prepared co-crystals.
31. • Drug with low solubility belonging to BCS class II (low solubility and high
permeability) is selected for the study.
• Since there is no literature support for the formation of co-crystals, there is scope
for obtaining the co-crystals with selected drug. Based on the literature review and
objective of the investigations, suitable experimental methods were developed for
evaluation.
31
33. 33
Equipments Sources
UV – Visible – Spectrophotometer – 1800 Shimadzu Corporation Tokyo, Japan
IR spectrophotometer Shimadzu Corporation Kyoto, Japan
Differential scanning calorimeter Sicco DSC calorimeter Module 7020 Japan
Melting point apparatus Biotech India Melting apparatus, Mumbai
Dissolution test apparatus Electrolab USP XXII scientific, Mumbai
Orbital shaking Incubator Remi industries, Kerala
Electronic balance – AUX-220 Shimadzu Corporation Tokyo, Japan
pH meter Elico LI 613
PXRD Shimadzu module XRD 7000, Japan
Tapped density apparatus DBK tapped density apparatus
Particle size analyzer Nanotrac W3275, Microtrac USA
Table 3-1: List of the equipments and their sources
34. 34
Property Literature data
Description Solid, yellow crystalline powder,
BCS class II drug
Chemistry 3⁰ Nitrogen, 5 fused ring system
Chemical nature Basic
Molecular weight 336.4 g/mol
Dose 150 mg
pKa 2.47
Log P 2.1
UV data λmax- 345 nm
IR (cm-1) 1505, 1271, 1234, 1030, 1098, 1587
Table 3-2: Properties of drug
35. 35
Indications: The drug sample has significant antimicrobial activity towards a variety of
organisms It has also been reported to have a multitude of biological effects, including
anti-malarial, anti-hypertensive, anti-lipidemic, anti-arrhythmic, anti-hyperglycemic,
anti-tumor, anti-inflammatory, anti-fungal, anti-HIV, antifungal, cardioprotective,
immunoregulative, anti-oxidative, and cerebro-protective activities.
36. 36
Pharmacokinetic properties:
Absorption: The drug has poor oral bioavailability which is attributed to its poor
aqueous solubility, low gastrointestinal absorption and dissolution.
Distribution: The organ distribution of drug is rapid with maximum distribution
in liver, followed by kidneys, muscle, lungs, brain, heart, pancreas and with least
distribution in fat where it remains relatively stable for 48 h.
Metabolism: Drug is metabolized in the liver, undergoing demethylation in phase
I followed by conjugation with glucuronic acid or sulfuric acid to form phase II
metabolites.
Excretion: Oral administration of drug resulted in excretion of drug and its
metabolites in bile, urine and feces.
37. Coformer
(Chemical formula)
Molecular
weight (g/mol)
pKa
Melting point
(0C)
Structure
Hydroquinone
(C6H6O2)
110.11 10.9 170-171
Succinic acid
(C4H6O4)
118.09 4.2 185-1870C
Adipic acid
(C6H10O4)
146.14 4.43 152.1
Benzoic acid
(C7H6O2)
122.12 4.19 122.41
Boric acid
(H3BO3)
61.83 9.24 171
37
Table 3-3: List of the coformers used in preparing co-crystals
40. • Melting point: The melting point of the drug was determined using capillary
tubes. The sample was filled and placed in the melting point apparatus. The
observed melting point was noted .
• FTIR Studies: Drug was mixed with KBr in definite ratio and compacted. The
spectrum was recorded in the wavelength region of 4000–400 cm−1. The
characteristic bands were identified and compared with literature data.
• DSC Studies: Powder drug sample was weighed and taken into an aluminium
pan and analyzed at a rate of 10 ºC per min from 0 – 300 ºC with nitrogen
purging and empty aluminium pan was used as reference. DSC thermogram
was recorded.
40
41. UV Scan for determination of λmax of drug:
10 mg drug sample was dissolved in 10ml methanol (1000 µg/ml). From the
above stock solution, 1 ml solution was diluted and volume was made up to 100
ml with 0.1 N HCl solution (10 µg/ml) and was scanned in UV
spectrophotometer.
41
42. Calibration curve of drug in 0.1N hydrochloric acid solution:
• 10 mg of pure drug was accurately weighed and dissolved in 10 ml methanol (1000
µg/ml). [Primary stock solution]
• From the above stock solution, 1 ml solution was diluted to 10 ml with 0.1 N HCl
solution to give 100 µg/ml concentration. [Secondary stock solution]
• From secondary stock solution i.e., 100 μg/ml concentration solution - 2, 4, 6, 8, 10,
12 and 14 μg/ml concentrations were prepared by using 0.1 N HCl solution. The
absorbance of these solutions were measured at 345 nm.
42
44. 44
Name
pKa of drug/
coformer
ΔpKa (pKa drug – pKa coformer)
Cinnamic acid 4.46 -1.99
Maleic acid 1.93 0.54
Boric acid 9.24 -6.77
Tartaric acid 1.5 0.97
L - Glutamic acid 2.23 0.24
D - Mannitol 13.5 -11.03
p- Amino Benzoic acid 4.65 -2.18
3,5-Dihydroxybenzoic Acid 5.4 -2.93
45. Solvent drop grinding method: Drug (1mmol) and different coformers (1mmol)
were taken and mixed in a mortar pestle using ethanol (2-3 drops) as solvent. The
triturating process was carried out for 30-45 mins. The formation of new co-crystal
was confirmed by melting point, FTIR, PXRD and DSC.
45
46. 46
10mg of drug in 10ml
volumetric flask. Make up
the volume with methanol.
(1000µg/ml)
Pipette 1 ml in 10ml
volumetric flask & make
up the volume with 0.1N
HCl. (100µg/ml)
Pipette 1 ml in 10ml
volumetric flask & make
up the volume with 0.1N
HCl. (10µg/ml)
and scanned at 345 nm
10mg of coformer in 10ml
volumetric flask. Make up
to 10ml with 0.1N HCl.
(1000µg/ml)
Pipette 1 ml in 10ml
volumetric flask & make
up the volume with 0.1N
HCl. (100µg/ml)
Pipette 1 ml in 10ml
volumetric flask & make
up the volume with 0.1N
HCl. (10µg/ml) and
scanned at 345 nm
Pipette 1 ml each from
individual 100 µg/ml standard
stock solution of drug and
coformer in 10ml volumetric
flask & make up the volume
with 0.1N HCl. (100µg/ml)
Pipette1 ml in 10ml volumetric
flask & make up the volume
with 0.1N HCl. (10µg/ml) and
scanned at 345 nm
Figure 3-1: Schematic representation of preparation of standard stock solution (10 μg/ml) of
drug (a), coformer (b) and drug and coformer mixture (c) in 0.1 N HCl solution
(a) (b) (c)
47. 47
•Melting point
•FTIR: The possible interaction between drug and coformers (catechol, mannitol) were
studied by IR spectroscopy.
•Powder X-Ray Diffraction (PXRD): PXRD gives a unique fingerprint diffraction
pattern characteristic of particular solid form. If a co-crystal has been formed between
two solid phases, the diffraction pattern of prepared co-crystal should be clearly
distinct from drug and coformer by the superimposition of PXRD pattern.
•Differential Scanning Colorimeter (DSC): DSC gives an accurate value for melting
onset temperature. DSC data is particularly valuable in constructing semi quantitative
energy-temperature relationship.
•Particle size
•Micromeritic Properties
48. • Saturation solubility studies: Excess of drug (pure drug) and drug co-crystals
were dissolved in 10 ml pH 1.2 buffer, and 10 ml water. The flasks were agitated in
orbital shaker at 25 ºC at 100 rpm for 24 h. After attainment of equilibrium, aliquots
were withdrawn, filtered and were diluted with pH 1.2 buffer, water accordingly
and were analyzed at 345 nm.
• Estimation of drug content in co-crystals: Drug content was determined by
dissolving 10 mg of co-crystal in 100 ml of 0.1N HCl. From the above solution 1ml
was pipette out and volume was made up to 10 ml using 0.1N HCl, which yields
sample of concentration 10 µg/ml. The samples were analyzed at 345 nm.
48
49. 49
• Dissolution Studies: Pure drug and various co-crystals containing the drug
equivalent to 5.3 mg were taken and filled in hard gelatin empty capsules.
Dissolution studies were carried out in 900 ml of pH 1.2 buffer solution,
temperature was maintained at 37 ± 0.5 ºC and 50 rpm was used. Samples were
withdrawn at time intervals of 10, 20, 30, 40, 50, 60,70, 80, 90 and 120 minutes.
The samples were filtered through 0.45μm filter and analyzed
spectrophotometrically at 345 nm.
• Comparison of Dissolution Profiles:
• Dissolution Efficiency and Mean Dissolution Time: It is defined as the area
under the dissolution curve up to certain time, t, expressed as a percentage of the
area of the rectangle described by 100% dissolution in same time.
• Mean dissolution time:
• Mean dissolution time reflects the time for the drug to dissolve in vivo.
50. D.E. =
MDT in vitro =
Similarity Factor and Difference Factor: The factor f2 measures the closeness
between the two profiles, with emphasis on the larger difference among all time
points.
f2 = 50 x
Difference factor:
It measures the percent error between two curves over all time points.
f1 =
50
52. 52
Melting Point
The melting point of the drug was determined using capillary tube. The drug
showed a melting range of 195-205 °C followed by decomposition. Similar
result was observed during DSC studies as shown in Figure 4-2.
53. 53
Figure 4-1: FTIR spectrum of pure drug
Fourier Transform Infrared Spectroscopy
55. 55
Figure 4-2: DSC thermogram of pure drug at heating rate of 10 ºC per min
Differential Scanning Calorimetry
56. 56
Figure 4-3: UV scan of drug solution (10 μg/ml) in 0.1 N HCl (max = 345 nm)
57. 57
Concentration
(μg/ml)
Absorbance at 345 nm
(AM±S.D)*
0 0.000 ± 0.000
2 0.153 ± 0.015
4 0.319 ± 0.019
6 0.479 ± 0.032
8 0.601 ± 0.033
10 0.763 ± 0.048
12 0.930 ± 0.044
14 1.077 ± 0.054
Table 4-2: Data for standard plot of drug in 0.1 N HCl at 345 nm
*Mean of three determinations
58. Figure 4-4: Standard plot of drug in 0.1 N HCl solution at 345 nm
58
y = 0.076x + 0.003
R² = 0.999
0
0.2
0.4
0.6
0.8
1
1.2
0 2 4 6 8 10 12 14 16
Concentration (μg/ml)
Absorbance
59. - ∆pKa
• The ΔpKa values were considered as a reference to predict, whether salts or co-
crystals will form. The pKa values of the drug and coformers were compiled
and ΔpKa values were calculated and summarized in Table 3-4.
• The ΔpKa values of formed adduct were less than 3 which implies salt or co-
crystal formation, but is not definitive.
59
61. 61
Figure. 4-6.1: UV absorption spectrum of drug,
mannitol and a mixture of drug-mannitol (10
µg/ml each) at 345 nm
Figure. 4-6.2: UV absorption spectrum of drug,
catechol and a mixture of drug-catechol (10
µg/ml each) at 345 nm
62. 62
Figure. 4-6.4: UV absorption spectrum of
drug, 3, 5 dihydroxy benzoic acid and a
mixture of drug- 3, 5 dihydroxy benzoic acid
(10 µg/ml each) at 345 nm
Figure. 4-6.3: UV absorption spectrum of drug,
tartaric acid and a mixture of drug-tartaric acid
(10 µg/ml each) at 345 nm
63. 63
Figure. 4-6.6: UV absorption spectrum of drug,
cinnamic acid and a mixture of drug-cinnamic
acid (10 µg/ml each) at 345 nm
Figure. 4-6.5: UV absorption spectrum of drug,
benzoic acid and a mixture of drug-benzoic
acid (10 µg/ml each) at 345 nm
64. Compound
Melting point, 0C
(Literature value)
Drug/co-crystal melting
range, 0C
(Observed value)
Drug
200.2
(Confirmed by DSC)
195-205 (followed by
decomposition)
Drug-mannitol 166-168 (Coformer)
150-158 (Red colour liquid
followed by decomposition)
Drug-catechol 105 (Coformer)
170-180 (followed by
decomposition at 200)
Drug-tartaric acid 206 (Coformer)
155-160 (followed by
decomposition at 210)
Drug-3,5 DHBA 237 (Coformer)
115-125 (orange colour liquid
followed by decomposition at
200)
Drug-benzoic acid 122.4 (Coformer)
95-100 (followed by
decomposition)
Drug-cinnamic acid 133 (Coformer)
90-100 (orange colour liquid
followed by decomposition at
183) 64
Table 4-3: Melting point values of drug, coformers and prepared co-crystals
70. 70
Figure 4-7.5: FTIR spectral comparison of drug, drug-benzoic acid co-crystal and
benzoic acid
71. 71
Figure 4-7.6: FTIR spectral comparison of drug, drug-cinnamic acid co-crystal and
cinnamic acid
72. 72
Drug Characteristic bands, cm-1 Inference
Drug
C=C Aromatic – 1506.4
C-N (stretching) – 1273.0
C=N – 1363.6
C-O – 1037.7
C-Cl (bending) – 827.4
O-H (stretching) – 3387.0
Characteristic peaks have been
observed
Name of co-crystals Characteristic bands, cm-1 Inference
Drug-mannitol
C=C Aromatic – 1506.4
C-N (stretching) – 1276.8
C=N – 1363.6
C-O – 1037.7
C-Cl (bending) – 839.0
O-H (stretching) – 3336.8
O-H, C-Cl, C-N shift has been
observed. Co-crystals might have
formed
Drug-catechol
C=C Aromatic – 1504.4
C-N (stretching) – 1276.8
C=N – 1367.5
C-O – 1043.4
C-Cl (bending) – 817.8
O-H (stretching) – 3446.7
Shift has been observed in all
absorption bands. Co-crystals
might have formed
Table 4-4: FTIR bands for characteristic changes of drug co-crystals
73. 73
Name of co-crystals Characteristic bands, cm-1 Inference
Drug-tartaric acid
C=C Aromatic – 1506.4
C-N (stretching) – 1274.9
C=N – 1363.6
C-O – 1037.0
C-Cl (bending) – 840.9
O-H (stretching) – 3317.0
O-H, C-Cl, C-N shift has been
observed. Co-crystals might have
formed
Drug-3, 5 di hydroxy
benzoic acid
C=C Aromatic – 1506.4
C-N (stretching) – 1273.0
C=N – 1361.7
C-O – 1037.7
C-Cl (bending) – 850.6
O-H (stretching) – 3217.2
O-H, C-Cl, C=N shift has been
observed. Co-crystals might have
formed
74. 74
Name of co-crystals Characteristic bands, cm-1 Inference
Drug-benzoic acid
C=C Aromatic – 1506.4
C-N (stretching) – 1273.0
C=N – 1363.6
C-O – 1037.7
C-Cl (bending) – 827.4
O-H (stretching) – 3334.9
Slight shift has been observed.
Might be a physical mixture
Drug-cinnamic acid
C=C Aromatic – 1506.4
C-N (stretching) – 1276.8
C=N – 1363.6
C-O – 1037.7
C-Cl (bending) – 840.9
O-H (stretching) – 3332.9
O-H, C-Cl, C-N shift has been
observed. Co-crystals might have
formed
75. 75
Figure 4-8.1: Overlay of the PXRD pattern of drug – mannitol co-crystal with its
individual components
76. 76
Figure 4-8.2: Overlay of the PXRD pattern of drug – catechol co-crystal with its
individual components
77. 77
Figure 4-8.3: Overlay of the PXRD pattern of drug- tartaric acid co-crystal
with its individual components
78. 78
Figure 4-8.4: Overlay of the PXRD pattern of drug- 3, 5 dihydroxy
benzoic acid co-crystal with its individual components
79. 79
Figure 4-8.5: Overlay of the PXRD pattern of drug- benzoic acid co-crystal with its
individual components
80. 80
Figure 4-8.6: Overlay of the PXRD pattern of drug- cinnamic acid co-
crystal with its individual components
81. 81
Name of co-
crystals
(Coformer 100%
intensity)
Peak 2θ value
Integrated
intensity of
Drug
Integrated
intensity of
Drug co-
crystals
Inference
Drug-mannitol
co-crystal
(Mannitol -18.79)
9.1
23.4
25.5
26.3
18.7
21.09
100
-
32.7
32.2
-
-
47.5
100
43.5
51
69.6
67
Change in
intensities and
formation of
new peaks was
observed
Drug-catechol co-
crystals
(Catechol-9.94)
5.8
8.2
9.1
25.5
26.3
-
-
100
32.7
32.2
93.6
100
-
92.6
45.5
Change in
intensities and
formation of
new peaks was
observed
Table 4-5: PXRD pattern comparison for characteristic changes of drug with drug co-
crystals
82. 82
Name of co-crystals
(Coformer 100%
intensity)
Peak 2θ value
Integrated
intensity of
Drug
Integrated
intensity of
Drug co-
crystals
Inference
Drug- tartaric acid
co-crystal
(Tartaric acid-20.82)
9.06
6.8
20.65
25.47
26.27
25.73
100
23.4
13.1
32.7
32.2
-
80.2
63.4
72.5
100
82.8
66.7
Change in
intensities were
observed and
formation of
new peak were
observed
Drug- 3, 5
dihydroxy benzoic
acid co-crystal
(3, 5 dihydroxy
benzoic acid-21.45 )
26.21
13.08
25.75
11.37
9.1
25.39
32.2
-
-
5.3
100
32.7
100
48.9
33.8
28.6
4.3
-
Change in
intensities and
formation of
new peak were
observed
83. 83
Name of co-
crystals
(Coformer 100%
intensity)
Peak 2θ value
Integrated
intensity of
Drug
Integrated
intensity of
Drug co-
crystals
Inference
Drug- benzoic
acid co-crystal
(Benzoic acid-
8.11)
8.08
9.097
17.16
26.29
6.84
-
100
-
32.2
23.4
100
66.6
58.2
52.8
38.8
Might be a
physical mixture
Drug- cinnamic
acid co-crystal
(Cinnamic acid-
9.75)
9.1
26.3
25.35
9.8
22.85
100
32.7
32.2
-
-
77.8
57.8
100
94.1
82.8
Change in
intensities were
observed and
formation of
new peak were
observed
89. 89
S.no Drug Melting point (ºC)
(literature value)
Peak (ºC)
(Observed value)
Inference
1 Drug - 200.2 -
S.no Name of co-crystal Melting point (ºC)
(literature value)
Peak (ºC)
(Observed value)
Inference
1 Drug-mannitol 166-168 159.3 Co-crystal might
have formed
2 Drug-catechol 105 180.2 Co-crystal might
have formed
3 Drug-tartaric acid 206
162.6
Co-crystal might
have formed
4 Drug-3, 5 di hydroxy benzoic
acid
237 116.09 Co-crystal might
have formed
5 Drug-cinnamic acid 133
158.4
Co-crystal might
have formed
Table 4-6: DSC changes of drug co-crystals
90. 90
Figure 4.10.1:Particle size distribution of the drug.
Figure 4.10.2:Particle size distribution of drug-mannitol co-crystals.
91. 91
Figure 4.10.3:Particle size distribution of drug-catechol co-crystals.
Figure 4.10.4:Particle size distribution of drug-tartaric acid co-crystals.
92. 92
Figure 4.10.5:Particle size distribution of drug-3,5 dihydroxy benzoic acid co-crystals.
Figure 4.10.6:Particle size distribution of drug-cinnamic acid co-crystals.
93. 93
Table 4-7: Comparison of micromeritic properties of drug and prepared co-crystals
Name
Bulk density
Tapped
density
Carr’s index
Hausners
ratio
Angle of
repose Property
(AM±S.D)*
Drug 0.25±0.005 0.40±0.01 37.5±0.005 1.57±0.04 - Very poor
Drug- mannitol
co-crystal
0.39±0.001 0.44±0.01 13.48±1.9 1.16±0.02 31.11±0.55 Good
Drug-catechol
co-crystal
0.49±0.01 0.54±0.01 9.91±0.003 1.11±0.002 16.88±0.81 Excellent
Drug- tartaric
acid co-crystal
0.45±0.01 0.52±0.01 13.52±0.27 1.16±0.003 34.60±1.62 Good
Drug- 3,5
dihydroxy
benzoic acid co-
crystal
0.53±0.03 0.62±0.01 10.27±0.01 1.11±0.02 21.36±2.95 Excellent
Drug- cinnamic
acid co-crystal
0.37±0.003 0.43±0.005 14.27±0.81 1.16±0.01 31.39±0.75 Good
*Mean of three determinations
94. Drug/co-crystal
Solubility studies (mg/ml) (AM±S.D)*
pH 1.2 Fold increase
Drug 0.0053±0.001 -
Drug-mannitol 0.0107±0.004 2.01
Drug-catechol 0.00829±0.001 1.57
Drug-tartaric acid 0.0084±0.001 1.58
Drug-3,5 DHBA 0.0095±0.001 1.79
Drug-cinnamic acid 0.0082±0.0009 1.56
94
Table 4-8: Solubility data of drug and drug co-crystals in pH 1.2
*Mean of three determinations
96. Drug/co-crystal
% Drug Content
(AM±S.D)*
Drug-mannitol 34.53±3.2
Drug-catechol 54.26±1.3
Drug-tartaric acid 61.39±4.61
Drug-3,5 DHBA 64.34±2.37
Drug-cinnamic acid 59.0±3.96
96
Table 4-9: Concentration of drug present in drug co-crystals
*Mean of three determinations
97. Medium pH 1.2
Volume of the medium 900 ml
Apparatus Type USP –II (Paddle)
Rpm 50
Dose Equivalent to 5.3 mg
Run time 120 minutes
Temperature 37 ± 0.5 ºC
Time Points 10, 20, 30, 40, 50, 60, 70, 80, 90 and 120 minutes.
λmax 345 nm
97
Table 4-10: Dissolution conditions
99. 99
Figure 4-11: Dissolution-time profile of drug and its co-crystals
0
20
40
60
80
100
120
0 20 40 60 80 100 120 140
Pure drug
Tartaric acid
3, 5 DHBA
Mannitol
Catechol
Cinnamic acid
Cumulativepercentagedrugdissolved
Time (mins)
100. 100
Drug/co-crystals
Drug dissolution analysis
Dissolution
efficiency (%)
Mean dissolution
time (min)
Similarity factor, f2 Difference factor, f1
Pure drug 34.48 39.91 - -
Drug- mannitol co-
crystal
73.04 13.75 11.0 71.60
Drug-catechol co-
crystal
81.23 20.94 15.35 59.0
Drug- tartaric acid
co-crystal
74.16 31.72 19.3 53.8
Drug- 3,5 dihydroxy
benzoic acid co-
crystal
61.93 30.35 27.4 45.2
Drug- cinnamic acid
co-crystal
67.13 29.85 23.5 49.4
Table 4-12: Dissolution efficiency, mean dissolution time (MDT) and similarity factor,
difference factor for drug and drug co-crystals.
101. • A UV spectrophotometric analytical method was developed for pure drug in 0.1 N
HCl. The λmax was found to be 345 nm, and Beer Lambert’s law was obeyed in the
range of 2 to 14 µg/ml (R2 = 0.999).
• UV spectral interference studies showed absence of interference at analytical
wavelength of the drug with coformer.
• Solvent drop grinding was opted for preparation of co-crystals with sixteen
different coformers.
• Based on ΔpKa and melting point co-crystals, the data suggested formation of five
co-crystals.
• IR studies showed slight changes in five drug co-crystals (catechol, mannitol,
cinnamic acid, tartaric acid and 3, 5 dihydroxy benzoic acid).
• The DSC exhibited the characteristic endothermic peak which was neither nearer to
the pure drug nor to the coformer in above five co-crystals.
101
102. 102
• Powder X-ray diffraction pattern of drug co-crystals with catechol, mannitol,
cinnamic acid, tartaric acid and 3, 5 dihydroxy benzoic acid, indicated the presence
of additional peaks and shifting of peaks when compared to pattern of drug.
• The saturation solubility study of all five co-crystals showed higher solubility in pH
1.2 than drug. Drug-mannitol co-crystals showed two-fold increase in solubility at
25 ºC in pH 1.2 (0.0107 mg/ml) when compared to that of drug (0.0053 mg/ml).
• The order of the dissolution of the co-crystal forms after 90 minutes was found to
be mannitol > tartaric acid > catechol > cinnamic acid > 3, 5 dihydroxy benzoic
acid > drug (pure drug). The 100% drug release was observed for drug-mannitol co-
crystals in 50 mins, while the pure drug showed only 51.66%.
103. 103
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105