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.
This slide contains the preformulation studies.It contains the various physicochemical properties that must be undergo to formulate the better absorption and stabiity of the different type of dosage form.This is ultimately used for the B Pharmacy final year students.Download the colourful ppt and enjoy the experience.
This slide contains the preformulation studies.It contains the various physicochemical properties that must be undergo to formulate the better absorption and stabiity of the different type of dosage form.This is ultimately used for the B Pharmacy final year students.Download the colourful ppt and enjoy the experience.
PHYSICAL AND CHEMICAL DEGRADATION OF PHARMACEUTICAL PRODUCTS.
Physical Factors
Loss of volatile constituents
Loss of water
Absorption of water
Crystal growth
Polymorphism changes
Colour changes
Chemical factors
Hydrolysis
Oxidation
Carboxylation
Decarboxylation
Isomerization
Polymerization
Solid dispersion is an effective way of improving the dissolution rate of poorly water soluble drugs and hence its bioavailability. The water soluble carriers used in preparation of solid dispersion enhance the dissolution rate of the poorly water soluble drug. This work reflects the improvement of Dissolution Characteristics as well as Bioavailability of poorly aqueous soluble drug Hydrochlorothiazide. It belongs to BCS class 2 i.e. it has poor water solubility but good permeability.
Formulation and Evaluation of Solid dispersion for Dissolution Enhancement of...Jing Zang
Nifedipine, a calcium channel blocker antihypertensive drug, is a poorly water soluble drug and belongs to BCS class II. The objective of the research work was to formulate and optimize solid dispersions (SDs) of a poorly water soluble drug, nifedipine, with sodium starch glycollate, croscarmellose sodium, eudragit E-100. Solid dispersions were prepared by solvent evaporation techniques in different weight ratios of polymers. The results indicated that homogeneous or heterogeneous conditions during the preparation methods employed governed the internal structures of the polymer matrices while retaining the drug in an amorphous form. The physical mixtures and solid dispersions were subjected to drug content and dissolution test. The best formulation, nifedipine with croscarmellose sodium in 1:7 ratio, among all was further adsorbed on neusilin US2 to form ternary mixture. The increased dissolution was achieved by more than 70percent and 30percent comparatively to the nifedipine API and marketed product respectively. The tablet dosage form prepared from ternary mixture was stable at stressed conditions 40±2°C and 75±5% RH. The release kinetics of drug from formulation and marketed product follows peppas model. The similar factor f2 was within limit for the product at stressed conditions with the product at room temperature at the same time.
PHYSICAL AND CHEMICAL DEGRADATION OF PHARMACEUTICAL PRODUCTS.
Physical Factors
Loss of volatile constituents
Loss of water
Absorption of water
Crystal growth
Polymorphism changes
Colour changes
Chemical factors
Hydrolysis
Oxidation
Carboxylation
Decarboxylation
Isomerization
Polymerization
Solid dispersion is an effective way of improving the dissolution rate of poorly water soluble drugs and hence its bioavailability. The water soluble carriers used in preparation of solid dispersion enhance the dissolution rate of the poorly water soluble drug. This work reflects the improvement of Dissolution Characteristics as well as Bioavailability of poorly aqueous soluble drug Hydrochlorothiazide. It belongs to BCS class 2 i.e. it has poor water solubility but good permeability.
Formulation and Evaluation of Solid dispersion for Dissolution Enhancement of...Jing Zang
Nifedipine, a calcium channel blocker antihypertensive drug, is a poorly water soluble drug and belongs to BCS class II. The objective of the research work was to formulate and optimize solid dispersions (SDs) of a poorly water soluble drug, nifedipine, with sodium starch glycollate, croscarmellose sodium, eudragit E-100. Solid dispersions were prepared by solvent evaporation techniques in different weight ratios of polymers. The results indicated that homogeneous or heterogeneous conditions during the preparation methods employed governed the internal structures of the polymer matrices while retaining the drug in an amorphous form. The physical mixtures and solid dispersions were subjected to drug content and dissolution test. The best formulation, nifedipine with croscarmellose sodium in 1:7 ratio, among all was further adsorbed on neusilin US2 to form ternary mixture. The increased dissolution was achieved by more than 70percent and 30percent comparatively to the nifedipine API and marketed product respectively. The tablet dosage form prepared from ternary mixture was stable at stressed conditions 40±2°C and 75±5% RH. The release kinetics of drug from formulation and marketed product follows peppas model. The similar factor f2 was within limit for the product at stressed conditions with the product at room temperature at the same time.
Preformulation and physicochemical property of the drugSHIVANEE VYAS
“It is the study of the physical and chemical properties of the
drug prior to compounding process”.
Preformulation commences when a newly synthesized drug shows sufficient pharmacologic promise in animal models towarrant evaluation in man.
These studies should focus on physicochemical properties of new compound that affect drug performance & development of efficaciouss dosage form.
This properties may provide;
A rationale for formulation design
Support the need for molecular modification.
It is a small presentation about the preformulation studies, which help students in their exams.
Preformulation is a crucial stage in pharmaceutical research and development that encompasses a series of scientific studies and experiments conducted before the formulation of a drug product begins. Its primary purpose is to gather essential information and data about the physical, chemical, and biopharmaceutical properties of a drug substance or active pharmaceutical ingredient (API).
Understanding the Drug Substance:
Preformulation starts with a comprehensive characterization of the drug substance. This includes identifying its chemical structure, molecular weight, and purity. Various analytical techniques are employed for this purpose, such as nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), and high-performance liquid chromatography (HPLC).
2. Assessing Physicochemical Properties:
Preformulation studies delve into the physicochemical properties of the drug substance. Researchers investigate properties such as solubility, melting point, crystallinity, hygroscopicity, and polymorphism. These properties can profoundly affect formulation design and stability.
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
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. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
2. NEW DRUG
• A change in a previously approved drug products formulation or method of
manufacture constitutes “newness”
• A combination of two or more old drugs or a change in the usual proportions of
drugs in an established combination product would be considered “new” if a
question of safety or efficacy is introduced by the change.
• A proposed new use for an established drug, a new dosage schedule or regimen
a new route of administration, or a new dosage form all cause a drug or drug
product to be “new” and reconsidered for safety and efficacy
3. SOME IMPORTANT FACTS OF NEW DRUG DISCOVERY
Only one drug in ten thousand can be successful.
ten to twelve years for a new drug to come in market.
In special circumstances FDA encourages fast tracking for
search of effective drugs to treat AIDS.
Drug discovery is designed to ensure that only safe and effective
pharmaceutical products are brought to market.
4. NEED TO DISCOVER NEW DRUG
To decrease adverse effects in currently available drugs
To increase bioavailability of existing drugs
Resistant drugs
Receptor based drugs
Difference in pharmacokinetics in different zones of people
5. NEW DRUG DISCOVERED
New drug discovery begins in lab with collective effort of scientists,
chemists and pharmacologists as they identify
Pharmaceutical Chemistry - Synthesis/modification
Pharmaceutical Analysis - Analytical method development
Pharmacology - Animal/Human volunteers study
Pharmaceutics - Formulation development
6. PREFORMULATION
Process of optimizing a drug through the determination and/or definition
of those physical and chemical properties considered important in the
formulation of a stable, effective and safe dosage form
Application of biopharmaceutical principles to physicochemical properties
Designing an optimum drug delivery system.
Characterization of drug molecule
Development of new dosage form.
First learning phase
7. INTRODUCTION
Late 1950’s and Early 1960 → Preformulation evolved
After 1960 → Pharmacokinetics and pharmacodynamics
developed, Analytical techniques were
improved and many organic compounds
were synthesized.
8. Long back
preformulation benefit of manufacturer.
Now → official requirement for IND (introductory new drug)
and NDA (New drug application)
IND involves description of the drug substance, and
its stability in the formulation.
IND required → approval by the FDA to market product.
9. GOALS OF PREFORMULATION
► To establish the physicochemical parameter of
new drug substances
► To establish the kinetic rate profile
► To establish physical characteristics
► To establish compatibility with the common excipients
10. The following events take place between the birth of
new drug molecule and marketing:
► Drug synthesized, tested for pharmacological activity
► Sufficient quantity is synthesized to
(i) perform initial toxicity studies
(ii) to do analytical work
(iii) to do initial preformulation studies
► Actual formulation is done
11. ► Formulation is subjected to phase 2 and phase 3 clinical
trials, during this period final formula is finalized
► NDA is submitted
► After approval of the NDA, production can be started
12. PRELIMINARY EVALUATION
1. Compound identity
2. Structure
3. Formula and molecular weight
4. Therapeutic indication
(a) Actual human dose
(b) Desired dosage form
(c) Bioavailability models
(d) Competitive products
5. Potential hazards
13. 6. Initial bulk lots
(a) Lot no.
(b) Crystallization solvent
(c) Particle size range
(d) Melting point
(e) % Volatile
(f) Observation
15. 8. Key dates
(a) Bulk scale up
(b) Toxicological start date
(c) Clinical supplies preparation
(d) IND filing
(e) Phase I testing
9. Critical development issue
16. MAJOR AREAS OF PREFORMULATION RESEARCH
I. Bulk characterization
Crystallinity and polymorphism
Hygroscopicity
Fine particle characterization
Powder flow properties
17. II. Solubility Analysis
Ionization Constant – pKa
pH Solubility Profile
Common Ion Effect – Ksp
Thermal Effects
Solubilization
Partition Coefficient
Dissolution
18. III. Stability Analysis
Stability in Toxicology Formulations
Solution Stability
pH Rate Profile
Solid State Stability
Bulk Stability
Compatibility
19. CRYSTALLINITIY AND POLYMORPHISM
Crystal habit and internal structure of a drug can affect
bulk and physicochemical properties, which ranges from
flowability to chemical stability.
21. Habit → outer appearance of a crystal
Internal structure → molecular arrangement within the solid
Changes with internal structure usually alter crystal habit.
Eg. Conversion of sodium salt to its free acid form produce
both a change in internal structure and crystal habit.
22. Crystals are characterized by repetitious spacing of constituent
atoms or molecules in a three dimensional array. In case of amorphous
forms atoms or molecules are randomly placed as in a liquid.
Amorphous forms - higher thermodynamic energy than the
crystalline form.
Upon storage, the amorphous forms tend to convert to more
stable crystalline forms.
Eg. Amorphous forms of Novobiocin was found to be well
absorbed, however when formulated into a suspension, convert into
more stable crystalline form and results in poor absorption
23. The parameters investigated are
Number of polymorphs that exist,
Relative degree of stability of various polymorphs,
Presence of a glassy state,
Stabilization of metastable forms,
Temperature stability ranges for each polymorph,
Solubility
24. Polymorphic stability - predicts long term physical stability of
dosage forms.
E.g.. Capping like cracking in tablets of anhydrous crystalline
carbochromen hydrochloride upon storage under high humidity
conditions. Due to transformation of the anhydrous form into a
dihydrate form.
25. The techniques used to study polymorphs are
1. Dissolution: Metastable forms are detectable because they
have a faster dissolution rate.
2. X ray diffraction:: Crystalline materials in powder form give
characteristic x ray diffraction patterns. Each powder pattern
of the crystal lattice is characteristic for a given polymorph.
3. Infra red spectroscopy: Different packing arrangements
will affect the energy of the molecular bonds thus altering
the IR spectra. Solid samples must be used since polymorphs
of a compound have identical spectra in solution.
26. 4. Differential scanning calorimetry and Differential thermal
analysis:
In these methods heat loss or gain resulting from physical
or chemical changes occurring in a sample is recorded as a
function of temperature as the substance is heated at uniform
temperature. Enthalpic changes i.e. both endothermic and
exothermic are caused by phase transitions. Fusion, sublimation,
solid-solid transition and water loss generally produce endothermic
effects while crystallization causes exothermic effects. Thermal
analysis enables evaluation of thermodynamic parameters
governing the system.
27. 5. Dilatometry:
Dilatometry measures the change in volume
caused by thermal or chemical effects. It has been used
to follow the melting behavior of theobroma oil by
measuring the specific volume of both rapidly and slow
cooled theobroma oil as function of increasing
temperature.
6. Hot stage microscope:
Upon heating to the phase transition point, the
crystal undergoes a change in the appearance.
28. Some problems in development that may result from inadequate
investigation of polymorphic drug forms are
1. Crystal growth in suspensions and creams, resulting in a product with
poor uniformity, appearance/bioavailability. E.g. Parenteral cortisone
acetate suspensions cake if prepared with the wrong polymorphic
form.
2. Precipitation of less soluble polymorphic form in liquid dosage forms.
3. Poor bioavailability from a less soluble polymorph, e.g.. Metastable
fluprednisolone implants has a higher absorption rate than the stale
form.
4. Crystal transitions resulting from milling or wet granulation, producing
changes in the physical nad biological characteristics of the dosage
form.
5. Poor chemical stability, eg. Amorphous penicillin is less stable than the
crystal salt.
29. Crystal habit may influence the properties as
1. Suspension stability and syringability: plate shaped crystals will
flow through a needle or orifice much more readily than needle
shaped crystals.
2. Tableting properties: Altered by crystal packing during
compression. E.g. particle size of lactose has a considerable
influence upon tablet strength.
3. Dissolution: Dissimilar crystalline habits may have different
dissolution rates depending on their surface area. Cubic and
spherical particles dissolve equally form all sides whereas other
habits change their shape factor during dissolution, altering the
dissolution rate.
30. Polymorphism effects on Dissolution:
Dissolution data for two polymorphs will be different when
more discriminating solvent is used. E.g. indole derivatives,
Crystal Characteristics and Bioavailability:
Different polymorphic forms of a given drug, show
difference in the dissolution rates and solubility. When absorption
of a drug is dissolution rate limited as more soluble and faster
dissolving form may be utilized to improve the rate and extent of
bioavailability.
31. E.g. Chloramphenicol palmitate
Comparative blood level data obtained in human following oral
administration of 1.5gm of pure A and pure B forms of chloramphenicol palmitate
and their mixtures chloramphenicol palmitate suspension containing varying ratios
of A and B polymorphs following single oral dose equivalent to 1.5 gm of
chloramphenicol.
Polymorph A 100% Polymorph B 0%
Polymorph A 75% Polymorph B 25%
Polymorph A 50% Polymorph B 50%
Polymorph A 25% Polymorph B 75%
Polymorph A 0% Polymorph B 100%
Among these pure polymorphic form B was most bioavailable.
32. Alpha and beta chlortetracycline hydrochloride
More soluble beta form is more bioavailable. The effect of
polymorphism on bioavailability is mediated via enhanced dissolution.
33. Crystal characteristics and chemical stability:
For drugs in solid state, the physical form of the drug
influences the rate of degradation.
For eg. Aztreonam, a monobactam antibiotic exists as needle like
and dense spherical beta crystalline forms. In the presence of high
humidity (37%°C / 75% RH). The crystalline forms undergoes beta
lactam hydrolysis more readily with shelf life of about 6 months
where as the beta form under identical condition is stable for
several years. Under stress condition anhydrous crystalline form of
the experimental drug degraded rapidly with a half life of 18
weeks. Solvate form of the drug under some condition was
essentially stable. The desolvated form degraded most rapidly.
34. Crystal characteristics and tabletting behavior
In a typical tableting operation, flow and compaction behaviors of the
powder mass to be tableted are important. These properties among
others are related to morphology, tensile strength, and density of the
powder bed. Two polymorphic forms of the same drug could differ
significantly respect to these properties. The morphology of a crystal also
depends on crystal habit. Crystal habit is a description of the outer
appearance of a crystal when the environment in which crystal grow
changes the external shape of the crystals without altering their internal
structure. The a different habit result. Crystal’s habit is influenced by the
presence of an impurity, concentration, rate of crystallization, and
hydrodynamics in crystallizer.
35. Crystal characteristic and physical stability
One form of the polymorphic form is thermodynamically stable at a
given temperature and pressure. The other forms would convert to the
stable form with time. This transformation may be rapid or slow. When
the transformation is not stable the thermodynamically is unstable form
is referred to us metastable form. The stable polymorph exhibits
highest melting point, the lowest solubility and the maximum chemical
and physical stability under shelf conditions to justify its use for reasons
of better dissolution or ease of tableting. Wherever metastable form is
remanded a Preformulation scientist must assure its integrity under a
variety of processing conditions.
36. Polymorphic transformation can occur during grinding,
granulating, drying and compressing. Digoxin, spironolactone, and
estradiol are reported to undergo, Polymorphic transformation during
size reduction. Phenylbutazone under goes polymorphic
transformation as a result of grinding and compression. Granulation
since it make use of a solvent molecule, can lead to solvate, formation.
A solvate molecule may change to anhydrous crystalline form, or
amorphic form in drying step.
37. HYGROSCOPICITY
THE AMOUNT OF MOISTURE ABSORBED BY THE FIXED WEIGHT OF ANHYDROUS
SAMPLE IN EQUILIBRIUM WITH THE MOISTURE IN THE AIR AT A GIVEN TEMPERATURE IS
REFERRED AS EQUILIBRIUM MOISTURE CONTENT. IT MAY INFLUENCE THE FLOW AND
COMPRESSION CHARACTERISTICS OF POWDER AND THE HARDNESS OF THE FINAL TABLET
AND GRANULATION PROCESS. MANY OF THE DRUG SUBSTANCES EXHIBIT A TENDENCY OF
ABSORBING MOISTURE. SO THESE HYGROSCOPIC COMPOUNDS SHOULD BE STORED IN A
WELL CLOSED CONTAINER. AND ALSO DURING PRODUCTION OF DOSAGE FROM USING
THESE COMPOUNDS THE HUMIDITY SHOULD BE MAINTAINED AT A CONTROLLED MANNER.
E.G. DURING CAPSULE FILLING 30-50% RELATIVE HUMIDITY IS MAINTAINED.
38. During reformulation the moisture content range should be
specified. If the granules have more moisture content it lead to poor
flow and excess hardness of the tablet. If the granules contain less
moisture, the compressed tablet may face problem of less hardness
and more friability. In such cases good packing like E.g. Strip or Blister
packing is essential. It is better to add silica gel packs in the bulk
container of tablet or capsules.
Deliquescent substances absorb water to dissolve completely.
E.g. sodium chloride. This hygroscopicity influence many important
parameters like chemical stability, flowability, and compatibility.
39. Test to find out hygroscopicity
1.Open containers :
Bulk drug is placed in open containers with a thin powder bed to assure
maximum atmospheric exposure. These samples are then exposed to a range of
controlled relative humidity. Moisture up-take should be monitored at time
points representative of handling (0 to 24 hrs) and storage (0 to 12 weeks).
2. Analytical method:
Gravimetry, Karl fisher titration gas chromatography etc
40. Types
1. Non hygroscopic If stored at RH < 90%, No moisture content increase.
If stored at RH > 90% for one week, moisture content increase up to < 20%.
2. Slightly hygroscopic If stored at RH < 80% No moisture content
increase. If stored at RH > 80% for one week, moisture content increase up to
< 40%.
3. Moderately hygroscopic If stored at RH < 60%, moisture content does
not increase above 5%. If stored at RH > 60% for one week, moisture content
increase up to < 50%.
4. Very hygroscopic If stored at RH as low as 40-50%, moisture content
may increase. If stored at RH > 90% for one week, moisture content may
exceed 30%.
41. BULK DENSITY
Bulk density of a compound varies with the method of
crystallization, milling, or formulation., Bulk density is of
importance in capsule filling and in selection of appropriate size
of the empty capsule and also in tablet granules flows into the
die. Usually bulk density is fo great importance when one
considers size of a high dose capsule product or homogeneity of
a low dose formulation in which there are large differences in
drug and excipients densities.
42. TYPES OF DENSITIES
1. True density: It is the ratio of weight to volume. It is
determined by liquid displacement method. (Helium
displacement method)
2. Granule density: The powder volume includes volume of
the particles with the intraparticle voids and this is
determined by mercury displacement method.
3. Bulk density: It is the weight of the powder divided by the
volume of the particle includes intra and inter particle voids.
Measured by tapping method.
43. PARTICLE SIZE
Particle size is characterized using these terms :
Very coarse
Coarse
Moderately coarse
Fine
Very fine
44. Particle size can influence variety of important factors :
- Dissolution rate
- Suspendability
- Uniform distribution
- Penetrability
- Lack of grittiness
45. Methods to Determine Particle Size
Sieving
Microscopy
Sedimentation rate method
Light energy diffraction
Laser holography
Cascade impaction
48. Color is generally a function of a drug’s inherent
chemical structure relating to a certain level of
unsaturation.
Color intensity relates to the extent of conjugated
unsaturation as well as the presence of chromophores.
Some compound may appear to have color although
structurally saturated.
COLOR
49. The substance may exhibit an inherent odor
characteristic of major functional groups present.
Odor greatly affects the flavor of a preparation or food
stuff.
TASTE:-
If taste is considered as unpalatable, consideration is
to be given to the use of a less soluble chemical form
of the drug.
The odour and taste may be suppressed by using
appropriate flavors and excipients or by coating the
final product.
ODOUR
50. POWDER FLOW PROPERTIES
Powder flow properties can be affected by change in particle
size, shape & density.
The flow properties depends upon following-
1. Force of friction.
2. Cohesion between one particle to another.
Fine particle posses poor flow by filling void spaces between
larger particles causing packing & densification of particles..
By using glident we can alter the flow properties.
e.g. Starch, Talc.
51. DETERMINATION OF POWDER FLOW PROPERTIES
By determining Angle Of
Repose.
A greater angle of repose
indicate poor flow.
It should be less than 30°.
& can be determined by
following equation.
tan θ = h/r.
where, θ = angle of repose.
h=height of pile.
r= radius.
Angle Of
Repose
( In degree)
Type Of Flow
<25 Excellent
25-30 Good
30-40 Passable
>40 Very poor
52. Carr’s Index Type of flow
5-15 Excellent
12-16 Good
18-21 Fair To Passable
23-35 Poor
33-38 Very Poor
>40 Extremely Poor
DETERMINATION OF POWDER FLOW PROPERTIES
53. SOLUBILIZATION
“ Solubilization is defined as the spontaneous passage
of poorly water soluble solute molecules into an
aqueous solution of a soap or detergent in which a
thermodynamically stable solution is formed ”.
54. When surfactants are added to the liquid at low
concentration they tend to orient at the air-liquid
interface .
On further addition of surfactant the interface
becomes completely occupied and excess molecules are
forced into the bulk of liquid.
At very high concentration surfactant molecules in the
bulk of liquid begin to form micelles and this
concentration is know as CRITICAL MICELLE
CONCENTRATION {CMC}
SOLUBILIZATION
55. The process of solubilization involves the breaking
of inter-ionic or intermolecular bonds in the solute,
the separation of the molecules of the solvent to
provide space in the solvent for the solute,
interaction between the solvent and the solute
molecule or ion.
Step 1: Holes opens in the solvent
56. Step2: Molecules of the solid breaks away from the
bulk
Step 3: The free solid molecule is intergraded into
the hole in the solvent
57. Description Parts of solvent required
for one part of solute
Very soluble < 1
Freely soluble 1 - 10
Soluble 10 - 30
Sparingly soluble 30 - 100
Slightly soluble 100 - 1000
Very slightly
soluble
1000 - 10,000
Insoluble > 10,000
58. Addition of co-solvent
pH change method
Reduction of particle size
Hydotrophy
Addition of Surfactant
Dielectrical Constant
Complexation
General Method of Increasing
the Solubility
59. e.g. Phenobarbitone is insoluble in water. A clear solution
is obtained by dissolving in mixture of Alcohol,
Glycerin, Propylene glycol.
e.g. Of Cosolvents:-
PG, glycerin, sorbitol, PEG, Glyceryl formal,
glycofurol, ethyl carbamate, ethyl lactate and dimethyl
acetamide.
Addition Of Co-Solvent
60. pH change Method
Weak base:- Alkaloids, Local Anaesthesia
Weak acid:- Sulphonamides, Barbiturates
In aqueous medium they dissociate poorly and
undissociated portion is insoluble.
e.g. Benzoic acid, Phenobarbitone
So, solubility of the undissociated portion is improved
by pH control.
For weak acidic drug:- increase pH, solubility is
increase.
For weak base drug:- decrease pH, increase solubility.
61. Reduction in Particle size improve solubility of drug.
Basically reduction in particle size increase contact
surface area of the particle, there by ultimately it
increase rate of solubility of drug.
Reduction Of Particle size
62. The term Hydotrophy has been used to designate the
increase in solubility in water of various substances due
to the presences of large amount of additives.
e.g. Solubilization of Benzoic acid with Sodium
benzoate.
Hydotrophy
63. Surfactants are molecules with well defined polar and
non-polar region that allow them to aggregate in solution
to form micelles. Non polar drugs can partition into
micelles and be solubilized.
e.g. Surfactant based solution of Taxol, that is
solubilized in 50% solution of Cremophor.
Addition of Surfactant
64. Dielectrical Constant is the effect that substances has,
when it acts as a solvent on the case with which it
separates oppositely charged atoms.
e.g. DEC of Water- 80
Kerosene- 2
Glycerine- 48
Benzene- 2.2
Dielectrical Constant
65. Complexation
For the Complexation occur both drug and ligand
molecule should be able to donate or accept electrons.
The solubility of compound is the sum of solubility
of the compound and its complex.
e.g. HgI2 (Mercuric Iodide) is sparingly soluble in
water. Its solubility in water is increased by forming
complex with KI.
HgI2 +2KI K2HgI4 (water soluble)
66. SURFACTANT
Surfactants:-
are wetting agents that lower the surface
tension of a liquid, allowing easier spreading, and
lower the interfacial tension between two liquids.
Classification
Some commonly encountered surfactants of each
type include:
1. Ionic 2. Non ionic
Cationic
Anionic
Zwitterionic
67. HLB SCALE
Griffin in 1947 developed the system of the
hydrophilic-lipophilic balance [ HLB ] of surfactant.
The higher the HLB of the an agent, the more
hydrophilic it is.
Tween, polyoxyethylene derivative of the spans are
hydrophilic and have high HLB value (9.6-16.7)
The lower the HLB of the agent, the more lipophilic
it is.
The sorbitan ester are lipophilic and have low HLB
value (1.8-8.6)
68. HLB SCALE
Most antifoaming agents
W/O Emulsifying agents
Wetting and Spreading agents
O/W Emulsifying agents
Detergents and Solubilizing agents
0
3
6
9
12
15
18
69. STABILITY
Provide a evidence on how the quality of a drug
substance or drug product varies with time under the
influence of a variety of environmental factors such
as….. temperature, Humidity and light.
Establish a re-test period for the drug substance or a
shelf life for the drug product and recommended storage
conditions.
Because physical, chemical or microbiological changes
might impact the efficiency and security of the final
product
04/05/2012
70. WHERE AND WHY?
Stability Studies are preformed on ...
Drug Substances (DS) The unformulated drug
substance that may subsequently be formulated with
excipients to produce the dosage form.
Drug Products (DP) The dosage form in the final
immediate packaging intended for marketing…….
controlled and documented determination of
acceptable changes of the drug substance or drug
product
71. WHAT ARE CHANGES?
Physical changes
• Appearance
• Melting point
• Clarity and color of solution
• moisture
• Crystal modification (Polymorphism)
• Particle size
Chemical changes
• Increase in Degradation
• Decrease of Assay
Microbial changes
72. FORCED DEGRADATION STUDIES
Acidic & Basic conditions.
Dry heat exposure
UV radiation exposure
Influence of pH
Influence of temperature
Influence of ionic strength
73. STABILITY STUDIES AT DIFFERENT STAGES
Stress- and accelerated Testing with drug substances
Stability on pre-formulation batches
Stress testing on scale-up Batches
Accelerated and long term testing for registration
On-going Stability testing
Follow-up Stabilities
74. Scope
• Solubility Profile
• Hygroscopicity
• Thermal stability
(Melting point,
Polymorphism)
• Chemical stability
1 Batch
Up to 3 month
Scope
• Determination of expire date
• Determination of preliminary
specifications
• Release of clinical batches
• Monitoring of samples during the clinical
phases
• Definition of storage conditions
• Definition of Tests for registration
stability
Up to 36 month
Selection of samples
• API, excipient, batches
Scope
• Appearance
• Appropriate physical-chemical parameter
• Assay / Degradation products
Up to 3 month
STABILITY STUDIES AT DIFFERENT STAGES
75. TESTING SCOPE FOR SOLID DOSAGE
Physical-chemical properties
– Appearance
– Elasticity
– Mean mass
– Moisture
– Hardness
– Disintegration
– Dissolution
Chemical properties
– Assay
– Degradation
Microbial properties
Container closure system properties
– Functionality tests (e.g. extraction from blister)
Tablet & Capsule
76. TESTING SCOPE FOR ORAL LIQUID FORM
Physical-chemical properties
– pH
– Color & clarity of solution
– Viscosity
– Particle size distribution (for oral suspensions only)
Chemical properties
– Assay
– Degradation products
– Degradation preservatives
– Content antioxidants
Microbial properties
Container closure system properties
– Functionality tests
77. TESTING SCOPE FOR
LIQUID FORMS FOR INJ. AND PARENTRAL
Physical-chemical properties
– pH
– Loss on weight
– Color & clarity of solution
Chemical properties
– Assay
– Degradation products
– Degradation preservatives
– Content antioxidants
Microbial properties
Container closure system properties
– Functionality tests
78. TESTING SCOPE FOR
SEMI LIQUID FORMS
Physical-chemical properties
– Appearance, odor, homogenesity, consistency
– Loss on weight, Viscosity
– Content uniformity (within the container)
Chemical properties
– Assay
– Degradation products & preservatives
– Content preservatives
– Degradation– Content antioxidants
Microbial properties
Container closure system properties
– Functionality tests
79. Study Storage condition
Minimum time period
covered by data at
submission
Long term 25°C ± 2°C / 60% ± 5% r.h or
30°C ± 2°C / 65% ± 5% r.h.
12 months
Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months
Accelerated 40°C ± 2°C / 75% ± 5% r.h. 6 months
Drug substances - General case
Drug substances - intended for storage in a Refrigerator
Study Storage condition Minimum time period
covered by data at
submission
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C / 60% ± 5% r.h. 6 months
80. Drug substances/Product- intended for storage in Freezer
Study Storage condition Minimum time period
covered by data at
submission
Long term -20°C ± 5°C 12 months
Drug products - General case
Study Storage condition Minimum time period
covered by data at
submission
Long term 25°C ± 2°C / 60% ± 5% r.h. or
30°C ± 2°C / 65% ± 5% r.h.
12 months
Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months
Accelerated 40°C ± 2°C / 75% ± 5% r.h. 6 months