Preformulations lecture 3
-
Upload
zameer-ul-hassan -
Category
Healthcare
-
view
1.610 -
download
0
description
Transcript of Preformulations lecture 3
![Page 1: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/1.jpg)
Dosage Form Design: Pharmaceutical and Formulation Considerations
![Page 2: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/2.jpg)
Dosage Form Design: Pharmaceutical and Formulation Considerations
Following considerations are involved in designing a dosage form:
General considerations in dosage form design
The need for dosage formsPharmaceutical ingredients and excipients
![Page 3: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/3.jpg)
PILOT-PLANT SCALE UPPLANT:It is a place were the 5 M’s (Alphabet M) like money,
material, man, method and machine are brought together for the manufacturing of the products.
PILOT-PLANT:It is the part of the pharmaceutical industry where a
lab scale formula is transformed into a viable product by development of liable and practical procedure of manufacture.
![Page 4: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/4.jpg)
SCALE-UP:The art for designing of prototype using the data
obtained from the pilot plant model.PROTOTYPE DRUG:A prototype drug is a sample of the drug used in
experiments to see how the drug acts and whether or not it does what it is supposed to do. It is also known as an experimental drug.
OBJECTIVES OF PILOT PLANT SCALE UP STUDY:To try the process on a model of proposed plant
before committing large sum of money on a production unit.
![Page 5: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/5.jpg)
Examination of the formula to determine it’s ability to withstand Batch-scale and process modification.
Evaluation and Validation for process and equipments To identify the critical features of the process.Guidelines for production and process controls.To provide master manufacturing formula with
instructions for manufacturing procedure.
![Page 6: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/6.jpg)
Why conduct Pilot Plant Studies? A pilot plant allows investigation of a product and process on
an intermediate scale before large amounts of money are committed to full-scale production It is not possible to design a large scale processing plant from laboratory data alone with any degree of success
A pilot plant can be used for Evaluating the results of laboratory studies and making product and process corrections and improvements
Producing small quantities of product for sensory, chemical, microbiological evaluations, limited market testing or furnishing samples to potential customers, shelf-life and storage stability studies
Providing data that can be used in making a decision on whether or not to proceed to a full-scale production process; and in the case of a positive decision, designing and constructing a full-size plant or modifying an existing plant
![Page 7: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/7.jpg)
General Considerations in Dosage Form DesignThe following considerations are used in
designing a dosage form.1)Preformulation Studies It includes the following:
Physical DescriptionMicroscopic ExaminationHeat of VaporizationMelting Point DepressionThe Phase RuleParticle SizePolymorphism
![Page 8: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/8.jpg)
SolubilitySolubility and Particle SizeSolubility and pHDissolutionMembrane PermeabilityPartition CoefficientpKa/Dissociation Constants
2)Drug and Drug Product Stability It involves the following important parameters.
Drug Stability: Mechanisms of DegradationDrug and Drug Product Stability: Kinetics
and Shelf LifeRate ReactionsEnhancing Stability of Drug ProductsStability Testing
![Page 9: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/9.jpg)
The Need for Dosage Forms
Besides providing the mechanism for the safe and convenient delivery of accurate dosage, dosage forms are needed for additional reasons:
1) Protection from oxygen and humidity (coated tablets, sealed ampules)
![Page 10: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/10.jpg)
2) Protection from gastric acid after oral administration (enteric-coated tablets)
3) To conceal the bitter, salty, or offensive taste or odor of a drug substance (capsules, coated tablets, flavored syrups)
![Page 11: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/11.jpg)
4)Insoluble drug substances can be solublized in a desired vehicle by formulating a suspension
Liquid preparation
insoluble unstable
in the desired vehicle
Suspension
![Page 12: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/12.jpg)
5) To provide rate-controlled drug action (various controlled-release tablets, capsules and suspensions)
6) To provide topical drug action from topical administration sites (ointments, creams, transdermal patches, ophthalmic, ear, and nasal preparations)
![Page 13: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/13.jpg)
7) To provide for the insertion of a drug into one of the body’s orifices (e.g., rectal or vaginal suppositories)
8) To provide for the placement of drugs directly into the bloodstream or into body’s tissues (e.g., injections)
![Page 14: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/14.jpg)
9) To provide for topical drug action through inhalation therapy(e.g., inhalants and inhalation aerosols)
![Page 15: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/15.jpg)
General Considerations in Dosage Form Design
![Page 16: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/16.jpg)
1)Physiological States Altering Response to Drugs
The following factors may alter response to drugs:Age (infants)Age (elderly)RaceBody weightTime of administrationToleranceTemperature
![Page 17: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/17.jpg)
2)Factors Affecting Drug Presentation to the BodyRoute of drug entry into the bodyPhysical form of the drug productDesign and formulation of the productMethod of manufacture of the productPhysicochemical properties of the drug and
excipientsPhysicochemical properties of the drug productControl and maintenance of location of drug at
the absorption siteControl of the release rate of the drug from the
drug product
![Page 18: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/18.jpg)
3)Design of Drug ProductsThe design of dosage form should be such that it
provides :EffectivenessSafetyReliabilityStability
PhysicalChemicalMicrobiological
![Page 19: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/19.jpg)
Pharmaceutical eleganceAppearanceOrganoleptic properties
ConvenienceEase of useDosing frequencyConsumer acceptance
![Page 20: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/20.jpg)
1)General Considerations in Dosage Form Design
It includes 2 important aspects which are asfollows:
Preformulation StudiesDrug and Drug Product Stability
![Page 21: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/21.jpg)
Preformulation StudiesIt includesChemical characterizationPhysical characterizationPhysical DescriptionSolids, liquids, gasesChemical Properties
Structure, form, reactivityPhysical Properties
Description, particle size, crystalline structure, melting point, solubility
Biological PropertiesAbility to get to site of action and elicit a response
![Page 22: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/22.jpg)
Microscopic ExaminationParticle sizeParticle size rangeCrystal structureParticle shape
Heat of VaporizationVapor pressureVolatile drugs can migrate within a solid dosage
formPersonnel exposure
![Page 23: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/23.jpg)
Melting Point DepressionPurity determinationIdentity
![Page 24: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/24.jpg)
Preformulation
Preformulation is branch of Pharmaceutical science that utilizes biopharmaceutical principles in the determination of physicochemical properties of the drug substance.
Prior to the development of any dosage form new drug, it is essential that certain fundamental physical & chemical properties of drug powder are determined .
This information may dictate many of subsequent event & approaches in formulation development.
This first learning phase is called as preformulation.
![Page 25: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/25.jpg)
INTRODUCTION
DEFINITION:-Investigation of physico-chemical properties of the new drug compound that could affect drug performance and development of an efficacious dosage form”.
Preformulation commences when a newly synthesized drug shows a sufficient pharmacologic promise in animal model to warrant evaluation in man.
![Page 26: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/26.jpg)
The preformulation is the first step in the rational development of a dosage form of a drug substance alone and when combined with excipients.
Objective :
To generate useful information to the formulator to design an optimum drug delivery system.
![Page 27: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/27.jpg)
GOALS OF PREFORMULATION
To establish the necessary physicochemical parameters of new drug substances.
To determine kinetic rate profile.To establish physical characteristics.To establish compatibility with common
excipients.
![Page 28: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/28.jpg)
General Considerations in Dosage Form Design
![Page 29: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/29.jpg)
1)Physiological States Altering Response to Drugs
The following factors may alter response to drugs:Age (infants)Age (elderly)RaceBody weightTime of administrationToleranceTemperature
![Page 30: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/30.jpg)
2)Factors Affecting Drug Presentation to the BodyRoute of drug entry into the bodyPhysical form of the drug productDesign and formulation of the productMethod of manufacture of the productPhysicochemical properties of the drug and
excipientsPhysicochemical properties of the drug productControl and maintenance of location of drug at
the absorption siteControl of the release rate of the drug from the
drug product
![Page 31: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/31.jpg)
3)Design of Drug ProductsThe design of dosage form should be such that it
provides :EffectivenessSafetyReliabilityStability
PhysicalChemicalMicrobiological
![Page 32: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/32.jpg)
Pharmaceutical eleganceAppearanceOrganoleptic properties
ConvenienceEase of useDosing frequencyConsumer acceptance
![Page 33: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/33.jpg)
1)General Considerations in Dosage Form Design
It includes 2 important aspects which are asfollows:
Preformulation StudiesDrug and Drug Product Stability
![Page 34: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/34.jpg)
Preformulation
Preformulation is branch of Pharmaceutical science that utilizes biopharmaceutical principles in the determination of physicochemical properties of the drug substance.
Prior to the development of any dosage form new drug, it is essential that certain fundamental physical & chemical properties of drug powder are determined .
This information may dictate many of subsequent event & approaches in formulation development.
This first learning phase is called as preformulation.
![Page 35: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/35.jpg)
INTRODUCTION
DEFINITION:-Investigation of physico-chemical properties of the new drug compound that could affect drug performance and development of an efficacious dosage form”.
Preformulation commences when a newly synthesized drug shows a sufficient pharmacologic promise in animal model to warrant evaluation in man.
![Page 36: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/36.jpg)
The preformulation is the first step in the rational development of a dosage form of a drug substance alone and when combined with excipients.
Objective :
To generate useful information to the formulator to design an optimum drug delivery system.
![Page 37: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/37.jpg)
GOALS OF PREFORMULATION
To establish the necessary physicochemical parameters of new drug substances.
To determine kinetic rate profile.To establish physical characteristics.To establish compatibility with common
excipients.
![Page 38: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/38.jpg)
Preformulation Studies
1) Physical description
The majority of drug substances in use today occur as solid materials. Most of them are pure chemical compounds of either crystalline or amorphous constitution.
![Page 39: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/39.jpg)
Preformulation StudiesBefore the formulation of a drug substance into a
dosage form, it is essential that it will be chemically and physically characterized.
Physical DescriptionSolids, liquids, gasesChemical Properties
Structure, form, reactivityPhysical Properties
Description, particle size, crystalline structure, melting point, solubility
Biological PropertiesAbility to get to site of action and elicit a response
![Page 40: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/40.jpg)
NEW DRUG DEVELOPMENT IN PREFORMULATION STUDIES
![Page 41: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/41.jpg)
PRE-FORMULATION STUDIES
Principle areas
Physico-chemical properties
Organoleptic properties
Particle size and shape
Purity
Surface area
Bulk characteriza
tion
Crystallinity and polymorphism
Hygroscopicity
Particle size characterization
Bulk density
Powder flow properties
Solubility analysis
Stability analysis
Ionization constant pka
PH solubility profile
Common ion effect
Thermal effects
Partition co-efficient
solubilization
Dissolution
Solution stability
Solid state stability
Bulk stability
Compatibilty
![Page 42: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/42.jpg)
![Page 43: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/43.jpg)
PRE-FORMULATION PARAMETERS
![Page 44: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/44.jpg)
ORGANOLEPTIC PROPERTIESCOLOURColor 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.Addition of colurant improves appearanceIdentification of colour is an important aspect of pre-
formulation studies
![Page 45: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/45.jpg)
ODOR 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 odor and taste may be suppressed by using appropriate
flavors and Excipients or by coating the final product.
![Page 46: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/46.jpg)
PURITYDesigned to estimate the levels of all known & significant
impurities & contaminants in the drug substance under evaluation.
Study performed in an analytical research & development group.
It is another parameter which allows for comparison with subsequent batches.
Occasionally, an impurity can affect stability.e.g. - Metal contamination
- Appearance
![Page 47: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/47.jpg)
The techniques used for characterizing the purity of a drug are the same as those used for other purpose in a preformulation study.
Thin layer chromatography is a wide ranging applicability & is an excellent tool for characterizing the purity.
HPLC, paper chromatography & gas chromatography are also useful.
More quantitative information can be obtained by using quantitative differential scanning colorimetry.
![Page 48: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/48.jpg)
Chemical properties Structure, form and reactivity
Physical properties
Physical description,Particle size,
Crystalline structure,Melting point,
Solubility
![Page 49: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/49.jpg)
Drugs can be used therapeutically as solids, liquids and gases. Liquids drugs are used to a much lesser extent than solid drugs; gases, even less frequently.
Many of the liquids are volatile substances and as such must be physically sealed from the atmosphere to prevent their loss.
Another problem associated with liquid drugs is that those intended for oral administration cannot generally be formulated into tablet form.
Formulation and stability difficulties arise less frequently with solid dosage forms than with liquid pharmaceutical preparations.
![Page 50: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/50.jpg)
MICROSCOPIC EXAMINATIONMicroscopic examination of the raw drug
substance is an important step in preformulation work.
It gives an indication of particle size and particle size range of the raw material as well as the crystal structure.
![Page 51: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/51.jpg)
PARTICLE SIZEVarious chemical and physical properties of drug
substances are affected by their particle size distribution and shapes.
The effect is not only on physical properties as well as biopharmaceutical behavior.
It also influence the flow and the mixing efficacy of powders and granules.
Fine materials are relatively more open to attack from atmospheric oxygen, humidity, than that of coarse material.
![Page 52: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/52.jpg)
PARTICLE SIZE Certain physical and chemical properties of drug
substances are affected by the particle size distribution, including drug dissolution rate, bioavailability, content uniformity, taste, texture, color and stability.
In addition, properties such as flow characteristics and sedimentation rates, among others, are also important factors related to particle size.
![Page 53: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/53.jpg)
Of special interest is the effect of particlesize on the drug’s absorption.
griseofulvinnitrofurantoinspironolactoneprocaine penicillin
![Page 54: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/54.jpg)
Particle size can influence variety of important factors :- Dissolution rate- Suspendability- Uniform distribution- Penetrability- Lack of grittiness
![Page 55: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/55.jpg)
Methods to Determine Particle Size
SievingMicroscopySedimentation rate methodLight energy diffractionLaser holographyCascade impaction
![Page 56: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/56.jpg)
1. Sieving method : Range : 50 – 150 µm Simple, inexpensive If powder is not dry, the apertures get clogged.2. Microscopy : Range : 0.2 – 100 µm Particle size can be determined by the use of
calibrated grid background. Most direct method. Slow & tedious method.
![Page 57: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/57.jpg)
4. Light energy diffraction : Range : 0.5 – 500 µm Particle size is determined by the reduction in light
reaching the sensor as the particle, dispersed in a liquid or gas, passes through the sensing zone.
Quick & fast.
5. Laser holography : Range : 1.4 – 100 µm A pulsed laser is fired through an aerosolized
particle spray & photographed in three dimensional with holographic camera, allowing the particles to be individually imaged & sized.
![Page 58: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/58.jpg)
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.
![Page 59: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/59.jpg)
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
![Page 60: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/60.jpg)
Determination Of Powder Flow Properties
Measurement of free flowing powder by compressibility. Also known as Carr's index.
CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY) X 100
TAPPED DENSITY
It is simple, fast & popular method of predicting powder flow characteristics.
![Page 61: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/61.jpg)
SURFACE AREAParticle size & surface area are inversely related to each
other.Smaller the drug particle, greater the surface area.
Specific surface is defined as the surface area per unit weight (Sw) or unit volume (Sv) of the material.
![Page 62: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/62.jpg)
MELTING POINT DEPRESSION
![Page 63: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/63.jpg)
A characteristic of a pure substance is a defined melting point or melting range. If not pure, the substance will exhibit a depressed melting point.
This phenomenon is commonly used to determine the purity of a drug substances before inclusion in the same dosage form.
![Page 64: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/64.jpg)
The melting point, or freezing point, of a pure crystalline solid is defined as that temperature where the pure liquid and solid exist in equilibrium.
The melting point/range of a drug can be used as an indicator of purity of chemical substances (a pure substance would ordinarily be characterized by a very sharp melting peak).
The addition of a second component to a pure compound (A), resulting in a mixture, will result in a melting point that is lower than that of the pure compound.
![Page 65: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/65.jpg)
The extent of lowering of the melting point is also related to the melting point itself.
- Compounds with low melting points are affected to a greater extent than compounds with high melting points upon the addition of a second component
- Low-melting-point compounds will result in a greater lowering of the melting point than those with high melting points.
![Page 66: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/66.jpg)
THE PHASE RULEPhase diagrams are often constructed to provide a visual
picture of the existence and extent of the presence of solid and liquid phases in binary, ternary and other mixtures.
A phase diagram, or temperature-composition diagram, represents the melting point as a function of composition of two or three component systems.
![Page 67: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/67.jpg)
Each phase is a homogenous part of the system, physically separated by distinct boundaries.
A description of the conditions under which these phases can exist is called the Phase Rule, which can be presented as: F=C-P+X
I
II
IV
III
T
![Page 68: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/68.jpg)
where F is the number of degrees of freedom. The degrees of freedom represent the environment conditions which can be independently varied without changing the number of phases in the system.
C is the number of components
P is the number of phases
X is a variable dependent upon selected considerations of the phase diagram (1, 2 or 3)
![Page 69: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/69.jpg)
POLYMORPHISM
![Page 70: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/70.jpg)
A crystal or crystalline solid is a solid material whose constituent atoms, molecules, or ions are arranged in an orderly repeating pattern extending in all three spatial dimensions.
An amorphous solid is a solid in which there is no long-range order of the positions of the atoms.
![Page 71: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/71.jpg)
An important factor on formulation is the crystal or amorphous form of the drug substance.
Polymorphic forms usually exhibit different physical-chemical properties including melting point and solubility.
The changes in crystal characteristics can influence bioavailability, chemical and physical stability, and have important implications in dosage form process functions.
![Page 72: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/72.jpg)
PHYSICOCHEMICAL CHARACTERISTICS UNDER PREFOFMULATION STUDIES
![Page 73: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/73.jpg)
SOLUBILITY ANALYSIS
![Page 74: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/74.jpg)
The solubility of drug is an important physicochemical property because It effects:
The rate of drug release into dissolution medium and consequently, the bioavailability of the drug,
Therapeutic efficiency of the pharmaceutical product.HOW TO DETERMNE SOLUBLITYSolubility is usually determined in variety of commonly
used solvents and some oils if the molecules are lipophilic. The solubility of material is usually determined by the equilibrium solubility method
![Page 75: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/75.jpg)
Common solvents used for solubility determination Benzyl Alcohol Isopropyl Alcohol
Tweens Polysorbates Castor Oil Peanut Oil Sesame Oil Propylene Glycol Glycerin Sorbitol Ethyl Alcohol Methanol
![Page 76: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/76.jpg)
AQUEOUS SOLUBILITYo A drug must possess aqueous solubility for therapeutic
efficacy in physiological pH o range of 1 to 8 at 37 ºC.o Poor solubility (<10mg/ml) may result into bioabsorption
problems.o If solubility of drug is less than 1 mg/ml it indicates the need
for a salt, particularly if o the drug will be formulated as a tablet or capsule.o In the range 1-10 mg/ml serious consideration should be
given to salt formation.
![Page 77: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/77.jpg)
There are 2 fundamental properties mandatory for a new compound.
[a] Intrinsic Solubility (Co):
Intrinsic solubility is the equilibrium solubility of the free acid or free base form of an ionisable compound at a pH where it is fully unionised (solubility of a neutral specie only)
The solubility of weakly acidic & weakly basic drug as a function of pH can be
predicted with the help of eqn.
S = Co {1 + (K1 / [H+])} --------- for weak acids.
S = Co {1 + ([H+] / K2)} -------- for weak bases.
![Page 78: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/78.jpg)
where,
S = Solubility at given pH
Co = Intrinsic solubility of the neutral form.
K1 = Dissociation constant of weak acid.
K2= Dissociation constant of weak base.The intrinsic solubility should ideally be measured at 2
temperatures:
a) 4 ºC → To ensure physical & chemical stability.
b) 37 ºC → To support biopharmaceutical evaluation.
![Page 79: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/79.jpg)
Method to determine solubility
(1) Equilibrium solubility method
(2) Turbid metric solubility method
(3) Nephlometric solubility method
(4) Ultrafiltration solubility method
(5) Direct solubility method
![Page 80: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/80.jpg)
IONIZATION CONSTANT (pKa):-It is the negative logarithm of dissociation constant. It describes about the chemical nature of Active
pharmaceutical ingredient. As it is known that 75 % of all drugs are weak bases, 25 % are weak acids and only, 5 % are nonionic amphoteric or alcohol.
![Page 81: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/81.jpg)
The unionized forms are more lipid soluble & more rapidly absorbed from g.i.t.
The relative conc. of unionized & ionized form of weakly acidic or basic drug in a solution at a given pH can be calculated using the Henderson- Hasselbalch equation:-
pH = pKa + log [unionized form] / [ionized form] ---- for weak bases.
pH = pKa + log [ionized form] / [unionized form] ---- for weak acids
![Page 82: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/82.jpg)
Uses of these equations:-1) To determine pKa.
2) To predict solubility at any pH provided that Co & pKa are known.
3) To facilitate the selection of suitable salt forming compounds.
4) It predicts the solubility & pH properties of the saltsLimitation:-To fall outside the pH limits of 4-10 or when the solution
is very dilute.
![Page 83: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/83.jpg)
Method to determine pKa:-
1) Potentiometric method.
2) Conductivity method.
3) Dissolution rate method.
4) Liquid-Liquid partition method.
5) Spectrophotometric method
![Page 84: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/84.jpg)
SOLUBLIZATION
![Page 85: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/85.jpg)
Many different approaches have been developed to improve drug solubility:
1) Micronization:-E.g. Griseofulvin shows increased solubility by reducing
particle size.
2) Change in pH:-E.g. Solubility of Nimesulide increases as pH is increased.E.g. Arginine increases solubility of coumarins.
![Page 86: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/86.jpg)
3) CosolvencyAddition of a water miscible solvent can often improve
the solubility of a weak electrolyte or nonpolar compound in water by altering the
polarity of the solvent.The choice of suitable cosolvent is limited for P’ceutical
use because of possible toxicity & irritancy.Ideally suitable blends should possess values of dielectric
constant between 25 -80.Commonly used cosolvents are ethanol, sorbitol, glycerin,
propylene glycol, dimethylacetamide (DMA), DMSO, etc.
![Page 87: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/87.jpg)
4) Solubilization by surfactantSolubility can be enhanced by the use of surfactants.E.g. Anionic & cationic surfactants exhibited dramatically
higher solubilization for gliclazide, while nonionic surfactants showed significantly lower solubilizing ability.
5) Complexation
Another way of increasing solubility.
E.g. The Complexation of iodine with 10-15% polyvinylpyrolidone (PVP) can improve
aqueous solubility of active agent.
![Page 88: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/88.jpg)
6)Chemical Modification:-Many poorly soluble drugs modified into salt form (water
soluble).
![Page 89: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/89.jpg)
PARTITION COEFFICIENT
![Page 90: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/90.jpg)
The gastrointestinal membranes are largely lipid in character hence the lipid solubility of a drug is an imp. factor in the assessment for its absorption potential.
When a solute is added to two immiscible liquids it will distribute itself between the two phases in a fixed ratio, which is referred to as partition or distribution coefficient.
It is independent of concentration of dilute solution of given solute species.
Various organic solvents used in determination of partition coefficient include Chloroform, ether, amyl acetate, etc.
![Page 91: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/91.jpg)
P > 1 Lipophilic drug.P < 1 Hydrophilic drugWhereP stands for partition co-efficientMethods to determine P:-
a) Shake Flask Method.
b) Chromatographic Method (TLC, HPLC).
c) Counter Current & Filter Probe method.
![Page 92: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/92.jpg)
Applications of P:-Measure of Lipophilic character of molecules.Recovery of antibiotics from fermentation broth.Extraction of drug from biological fluid for therapeutic
monitoring.Absorption of drug from dosage forms. (Ointments,
Suppositories, Transdermal patches).Study of distribution of flavoring oil between oil & water
in emulsion.
![Page 93: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/93.jpg)
THERMAL EFFECT
![Page 94: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/94.jpg)
Effect of temperature on the solubility of drug can be determined by measuring heat of solution. (∆Hs).
ln S = -∆Hs/RT + C.
where, S = Molar solubility at temperature T (K).
R = Gas constant. Heat of solution represents the heat released or absorbed
when a mole of solute is dissolved in a large quantity of solvent.
![Page 95: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/95.jpg)
Mostly solution process is endothermic (∆Hs = +ve) & thus increasing the solution
temperature increase the drug solubility.Typical temp. range should include 5°C, 25°C, 37°C &
50°CImportance: Determination of temperature effect on solubility helps in
predicting storage condition & dosage form designing
![Page 96: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/96.jpg)
COMMON ION EFFECT
![Page 97: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/97.jpg)
Addition of common ion reduces the solubility of slightly soluble electrolyte.
The “salting out” results from the removal of water molecules as solvent due to the competing hydration of other ions.
So weakly basic drug which are given as HCl salts have decreased solubility in acidic solution.
E.g. Chlortetracycline, Papaverine, Bromhexine, Triamterene, etc.
The reverse process “salting in” arises with larger anions. (E.g. Benzoate, salicylate) which can open the water structure.
These hydrotropes increase the solubility of poorly water soluble compounds
![Page 98: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/98.jpg)
DISSOLUTION
![Page 99: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/99.jpg)
The absorption of solid drugs administered orally can be understood by following flowchart.
Solid drugs in GI fluid
Solution of drug in GI fluid
Drug in systemic circulation
Kd
Dissolution
Ka
Absorption
![Page 100: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/100.jpg)
In many instances, dissolution rate in the fluids at the absorption site is the rate limiting step in the absorption process.
Dissolution rate can affect
- Onset of action.
- Intensity of action.
- Duration of response.
- Control the overall Bioavailability of drug form.
![Page 101: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/101.jpg)
Dissolution is to be considered of 2 types:
[1] Intrinsic dissolutionThe dissolution rate of solid in its own solution is known as
intrinsic dissolution and is described by Noyes-Whitney equation:
dC/dt = AD (Cs-C) / hv
where, dc/dt = Dissolution rate.
A = Surface area of dissolving solid.
D = Diffusion coefficient.
C = Concentration of drug in solution.
h = Thickness of diffusion layer (at the solid- liquid interface).
v = Volume of dissolution medium.
Cs = Solute concentration in the diffusion layer.
![Page 102: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/102.jpg)
This equation helps to the preformulation scientist in predicting if absorption would be dissolution rate limited or not.
Method to determine intrinsic dissolution:-Rotating disk method or Wood’s apparatus:
This method allows for the determination of dissolution from constant surface area, obtained by compressing powder into a disc of known area with a die-punch apparatus.
![Page 103: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/103.jpg)
2) Particulate dissolutionThis method determines the dissolution of solids at
different surface area.A weighed amount of powder sample from a particular
sieve fraction is introduced in the dissolution medium. Agitation is usually provided by a constant speed propeller.
It is used to study the influence on dissolution of particle size, surface area & mixing with excipients.
![Page 104: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/104.jpg)
STABILITY ANALYSIS
![Page 105: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/105.jpg)
Development of a drug substance into a suitable dosage form requires the
Preformulation stability studies of drug under the following categories:-
[1] Solid state stability.
[2] Solution state stability
![Page 106: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/106.jpg)
1] Solid state stabilitySolid state reactions are much slower & more difficult to
interpret than solution state reactions because of reduced no. of molecular contacts between drug & excipient molecules & occurrence of multiple reactions.
Techniques for solid state stability studies:Solid State NMR Spectroscopy. (SSNMR)Powder X-ray diffraction. (PXRD)Fourier Transform IR. (FTIR)Raman Spectroscopy.Differential Scanning Calorimetry (DSC).
![Page 107: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/107.jpg)
[2] Solution State StabilityThe primary objective is identification of conditions
necessary to form a solution.These studies include the effects of
- pH - Temperature. - Light - Oxygen. - Cosolvents - Ionic Strength.- Solution Stability investigations usually commence with
probing experiments to confirm decay at the extremes of pH & temperature.
- If the results of this solution stability studies dictate the compound as sufficiently stable, liquid formulation can be developed.
![Page 108: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/108.jpg)
Stress conditions used in preformulation stability assessment
TEST CONDITIONSOLID
Heat (°C) 4,20,30,40,40/75 % RH, 50 & 75.
Moisture uptake 30,45,60,75&90% RH at RT.
Physical stress Ball milling
AQUEOUS SOLUTION
pH 1,3,7,9 & 11 at RT & 37ºC.
Reflux in 1M HCl & 1M NaOH.
Light UV (254 & 366 nm) & Visible at RT.
Oxidation Sparing with oxygen at RT, UV may accelerate breakdown.
![Page 109: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/109.jpg)
In above mentioned table RH stands for relative humidity and RT stands for relative temperature.
![Page 110: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/110.jpg)
CHEMICAL CHARACTERISTICS
![Page 111: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/111.jpg)
1) OXIDATION
It is a very common pathway for drug degradation in liquid & solid formulation.
Oxidation occurs in two ways:-1. Auto oxidation2.Free radical chain processAuto oxidation:-It is defined as a reaction of any material with
molecular oxygen which produces free radicals by hemolytic bond fission of a covalent bond.
![Page 112: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/112.jpg)
These radicals are highly unsaturated & readily take electron from other substance causing oxidation.
For auto oxidation to occur in solid molecular oxygen must be able to diffuse through the crystal lattice to liable sites. Hence crystal morphology & packing are important parameters for determining oxidation kinetics.
![Page 113: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/113.jpg)
Free radical chain processIt involves the following steps:InitiationPropagationHydrogen peroxide decompositionTermination
![Page 114: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/114.jpg)
Functional groups having high susceptibility towards oxidation:-
- Alkenes. - Substituted aromatic groups. (Toluene,
phenols, anisole).- Ethers. - Thioethers.- Amines.
![Page 115: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/115.jpg)
Factors affecting oxidation process:-
1. Oxygen concentration.2. Light.3. Heavy metals particularly those having two
or more valence state. (E.g. Copper, iron, nickel, cobalt).4. Hydrogen & Hydroxyl ion.5. Temperature.
![Page 116: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/116.jpg)
Prevention of oxidation:-
1) Reducing oxygen contentOxidative degradation of drug takes place in
an aqueous solution, so the oxygen content can be decreased by boiling water.
2) Storage in a dark & cool condition3) Addition of an antioxidanta) Reducing agent.b) Chain inhibitors of radical induced
decomposition.
![Page 117: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/117.jpg)
ANTIOXIDANT
OIL SOLUBLE WATER SOLUBLE
Free radical acceptor & inhibit free radical chain process.
Examples α- Tocopherol, Hydroquinone, Propyl gallate, Butylated Hydroxyls Anisole (BHA), Butylated Hydroxy Toluene (BHT), Lecithin.
Oxidized itself & prevent oxidation of drug.
Examples Sodium met bisulphate, Sodium bisulphite, Acetyl cysteine, Ascorbic acid, Sodium thiosulfate, Sulphur dioxide, Thioglycolic acid, Thioglycerol.
![Page 118: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/118.jpg)
HYDROLYSIS It involves nucleophilic attack of labile groups. Eg. Lactam > Ester > Amide > Imide. When this attack is by a solvent other than water then it is known as solvolysis. It generally follows 2nd order kinetics as there are 2 reacting species,
water and API. In aqueous solution, water is in excess, the reaction is 1st order.
Conditions that catalyze the breakdown:-Presence of hydroxyl ion.Presence of hydride ion.Presence of divalent ion.Heat.Light.Ionic hydrolysis.Solution polarity & ionic strength.High drug concentration.
![Page 119: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/119.jpg)
Prevention of hydrolysis:-
pH adjustment.Formulate the drug solution close to its pH of optimum stability.Addition of water miscible solvent in formulation.Optimum buffer concentration to suppress ionization.
Addition of surfactant: Nonionic, cationic & anionic surfactant stabilizes the drug
against base catalysis.Salts & esters: E.g. Phosphate ester of Clindamycin.The solubility of p’ceuticals undergoing ester hydrolysis can be reduced by forming less soluble salts.
Store with dessicants.
By use of complexing agent.
![Page 120: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/120.jpg)
PhotolysisMechanism of decomposition:-
Electronic configuration of drug overlaps with spectrum of sunlight or any artificial light, & thereby energy is absorbed by electron & it goes to the excited state.
They are unstable & release the acquired energy & come to the ground state & decompose the drug.
![Page 121: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/121.jpg)
Photosensitization means molecule or excipient which absorbs energy but do not participate themselves directly in the reaction but pass the energy to other that will cause cellular damage by inducing radical formation.
Photosensitizer
Energy transfer Electron transfer
Convert oxygen from its ground state to singlet excited state.
Generate superoxide molecule, which is an anion radical & acts as a powerful oxidizing agent.
![Page 122: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/122.jpg)
PHOTODECOMPOSITION PATHWAYS
N-Dealkylation: Eg. Diphenhydramine, Chloroquine, Methotrexate.
Dehalogenation: Eg. Chlorpropamide, Furosemide.
Dehydrogenation of Ca++ channel blocker.Eg. Solution of Nifedipine → Nitrosophenylpyridine
(with loss of water).
Rapidly yellow color
Brown.
![Page 123: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/123.jpg)
Decarboxylation in anti-inflammatory agents.E.g. Naproxen, Flurbiprofen,
Oxidation.E.g. Chlorpromazine & other phenothiazines give N- & S- oxides in the presence of sunlight.
Isomerization & cyclization.E.g. Noradrenaline, Doxepine.
Rearrangement.E.g. Metronidazole → Oxidiazine → Yellow color.
Contd…
![Page 124: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/124.jpg)
Prevention of Photodecomposition:-
Suitable packing.Eg. Yellow-green glass gives the best protection in U.V.
region while Amber confers considerable protection against U.V. radiation but little from I.R.
Use of Anti-oxidant. Eg. Photodegradation of Sulphacetamide solution may be inhibited by an antioxidant such as sodium thiosulfate or sodium metabisulphate.
Protection of drug from light.Eg. Nifedipine is manufactured under sodium light.
![Page 125: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/125.jpg)
Avoiding sunbath. E.g. Sparfloxacin.
Photostabilizer [Light absorber].• Colorant Azorubine.• Pigments Iron oxide, Titanium dioxide.
Coating: Pigments like TiO2(IN NIFEDIPINE) / ZnO.E.g. Photo stabilization of Sulphasomidine Tablet by film coating containing U.V. absorber (Oxybenzone) to protect color & photolytic degradation.
![Page 126: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/126.jpg)
POLYMERIZATION
It is a continuous reaction between molecules.
More than one monomer reacts to form a polymer.
Eg. Shellac on aging undergoes polymerization & hence prolongs disintegration time &dissolution time.
![Page 127: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/127.jpg)
Hydrolysis and Oxidation are the most common pathways for API degradation in the solid-state and in solution.
Photolysis and trace metal catalysis are secondary processes of degradation.
Temperature affects each of the above chemical degradation pathways; the rate of degradation increases with temperature.
It is well understood that pH, particularly extremes, can encourage hydrolysis of API when ionised in aqueous solution. This necessitates buffer control if such a dosage form is required. pH within the micro-environment of a solid oral dosage form can also impact on the stability of the formulation where the API degradation is pH sensitive; through understanding the aqueous pH imparted by typical excipients, a prudent choice can overcome this issue.
According to W.H.O.
![Page 128: Preformulations lecture 3](https://reader036.fdocuments.in/reader036/viewer/2022081400/5549842fb4c905c26a8b4aa3/html5/thumbnails/128.jpg)
SUMMARY:
Preformulation studies, properly carried out, have a significant part to play in anticipating formulation problems and identifying logical paths in both solid and liquid dosage form.
Comparing physico chemical property with each drug candidate within a therapeutic group, the preformulation scientist can assist the synthetic chemist to identify optimum molecule, pharmacologist to suit the vehicle for electing desired p’cological response and the bulk pharmacist to select and produce best salt with proper p’cle size and morphology for subsequent processing.