Preformulation Studies Notes – Pharmaceutics B. Pharma 5th Semester

Preformulation Studies

Preformulation Studies Notes - Pharmaceutics B. Pharma 5th Semester

Preformulation Studies

Pre-formulation

It is defined as the phase of research and development in which preformulation studies characterize physical and chemical properties of a drug molecule in order to develop safe, effective and stable dosage form.

Preformulation testing is the first step in the rational development of dosage forms.

It can be defined as an investigation of physical and chemical  property of a drug substance alone and when combined with excipients.

NEED of Pre-Formulation Study 

Preliminary evaluation

Molecular optimisation

Suitability of Excipients

Suitability of dosage foam

Objective of Preformulation Studies

To establish the physico-chemical parameters of a new drug entity

To determine its kinetics and stability

To establish its compatibility with common excipients

It provides insights into how drug products should be processed and  stored to ensure their quality

Major Area of Preformulation  Research

➢ ORGANOLEPTIC CHARACTERS

➢ BULK CHARACTERS

❑ Crystallinty and polymorphism

❑ Hygroscopicity

❑ Fine particle characterization

❑ Powder flow properties

➢ SOLUBILITY ANALYSIS

❑ ionization constant-PKa

❑ pH solubility profile

❑ Common ion effect-Ksp

❑ Thermal effects

❑ Solubilization

❑ Partition co-efficient

❑ Dissolution

➢ STABILITY ANALYSIS

❑ Stability in toxicology formulations

❑ Solution stability

❑ pH rate profile

❑ Solid state stability

❑ Bulk stability

❑ Compatibility

ORGANOLEPTIC CHARACTERS

❖ Colour,odour, taste of the new drug must be  recorded

COLOUR            ODOUR              TASTE 

❑Off-white       ❑ pungent            ❑ Acidic

❑Cream yellow ❑ sulphurous      ❑ Bitter

❑tan                   ❑ Fruity             ❑ Bland

❑shiny               ❑ Aromatic        ❑ Intense

❑ Odourless       ❑ Sweet

❑ Tasteless

Preformulation Bulk Characterization 

Crystallinity

Crystal habit & internal structure of drug can affect bulk & physicochemical property of molecule.

Crystal habit is description of outer appearance of crystal.

Internal structure is molecular arrangement within the solid.

Change with internal structure usually alters crystal habit.

Eg. Conversion of sodium salt to its free acid form produce both change in  internal structure & crystal habit.

Different shapes of crystals

Different shapes of crystals

Depending on internal structure compounds is classified as

1. Crystalline

2. Amorphous

Crystalline compounds are characterized by repetitious spacing of constituent atom or molecule in three dimensional array.

In amorphous form atom or molecule are randomly placed.

Solubility & dissolution rate are greater for amorphous form than  crystalline, as amorphous form has higher thermodynamic energy.

Eg. Amorphous form of Novobiocin is well absorbed whereas  crystalline form results in poor absorption.

Polymorphism

It is the ability of the compound to crystallize as more than one  distinct crystalline species with different internal lattice.

Different crystalline forms are called polymorphs.

Polymorphs are of 2 types

1. Enatiotropic

2. Monotropic

The polymorph which can be changed from one form into another  by varying temp or pressure is called as Enantiotropic polymorph.

Eg. Sulphur.

One polymorph which is unstable at all temp. & pressure is called as Monotropic polymorph.

Eg. Glyceryl stearate.

Polymorphs differ from each other with respect to their physical property such as

• Solubility

• Melting point

• Density

• Hardness

• Compression characteristic

Eg. 1)Chloromphenicol exist in A,B & C forms, of these B form is  more stable & most preferable.

ANALYTICAL METHODS FOR THE  CHARACTERIZATION OF SOLID FORMS

  • Microscopy
  • Hot stage microscopy
  • Thermal analysis
  • X-ray diffraction
  • Infrared (IR) spectroscopy
  • Proton magnetic resonance (PMR)
  • Nuclear magnetic resonance (NMR)
  • Scanning electron microscopy (SEM)

Microscopy

Material with more than one refractive index are anisotropic & appear  bright with brilliant colors against black polarized background.

The color intensity depends upon crystal thickness.

Isotropic material have single refractive index and this substance do not  transmit light with crossed polarizing filter and appears black.

Advantage :

By this method, we can study crystal morphology & difference between   polymorphic form.

Disadvantage :

This require a well trained optical crystallographer, as there are many possible crystal habit & their appearance at different orientation.

Hot stage microscopy

The polarizing microscope fitted with hot stage is useful for investigating polymorphism, melting point & transition temp.

Disadvantage :

In this technique, the molecules can degrade during the melting  process.

Thermal analysis

Differential scanning calorimetry (DSC) & Differential thermal analysis  are (DTA) are particularly useful in the investigation of polymorphism.

It measures the heat loss or gain resulting from physical or chemical changes within a sample as a function of temp.

For characterizing crystal forms , the heat of fusion can be obtained  from the area under DSC- curve for melting endotherms.

Similarly, heat of transition from one polymorph to another may be  calculated.

A sharp symmetric melting endotherm can indicate relative purity of molecule.

A broad asymmetric curve indicates presence of impurities.

X-ray diffraction

X-ray diffraction

Working :

When beam of nonhomogenous X-ray is allow to pass through the crystal, X-ray beam is diffracted & it is recorded by means of photographic plate.

Diffraction is due to crystal which acts as 3 dimensional diffraction  grating toward X-ray.

Random orientation of crystal lattice in the powder causes the  X-ray to scatter in a reproducible pattern of peak intensities.

The diffraction pattern is characteristic of a specific  crystalline lattice for a given compound.

An amorphous form does not produce a pattern mixture of  different crystalline forms.

Single – Crystal x-ray provide the most complete information about the solid state.

HYGROSCOPICITY

Many drug substances, particularly water –soluble salt forms, have a tendency to adsorb atmospheric moisture.

Adsorption and moisture content depend upon the atmospheric humidity, temperature, surface area, exposure and the mechanism of moisture uptake.

The degree of Hygroscopicity is classified into four classes:

  • Slightly hygroscopic: increase in weight is ≥ 0.2% w/w and < 2% w/w
  • Hygroscopic : increase in weight is ≥ 0.2 % w/w and < 15 % w/w
  • Very hygroscopic : increase in weight is ≥ 15% w/w
  • Deliquescent : sufficient water is adsorbed to form a solution

Hygroscopicity is tested by:

  1. Samples are exposed to the moisture
  2. exposed to controlled relative humidity environments
  3. moisture uptake is monitored at different time points
Analytical methods which is used are :
  • Gravimetry
  • Karl Fischer Titration
  • Gas chromatography

PARTICLE SIZE

Particle size is characterized using these terms :

Very coarse, Coarse, Moderately coarse, Fine ,Very fine .

Particle size can influence variety of important factors :

  • Dissolution rate
  • Suspendability
  • Uniform distribution
  • Penetrability
  • Lack of grittiness

Methods to Determine Particle Size

  • Sieving (5µ-150µ)
  • Microscopy(0.2µ-100µ)
  • Sedimentation rate method(1µ-200µ)
  • Light energy diffraction(0.5µ-500µ)
  • Laser holography(1.4µ-100µ)

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. Talc

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

Methods to determine angle of  repose

➢ Static angle of  repose

  • Fixed-funnel  method
  • Fixed-cone method

➢ Kinetic or dynamic  method

  • Rotating cylinder  method
  • Tilting box method

Determination of Powder Flow Properties

➢ Measurement of free flowing powder by compressibility.

➢ Also knaown 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.

Determination of Powder Flow Properties

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

SOLUBILITY STUDIES

1. Solution phase equilibrium with solid phase at a stated temperature and  pressure.

2. Determines  amount  of drug dissolved  , amount  of drug available for  absorption.

3. Solubility reduction is carried out in certain conditions:

❖ Enhancement of chemical stability.

❖ taste masking products.

❖ Production of sustained release products.

Descriptive term                        Parts of solvent required for 1 part of solute

Very soluble                                                         Less than 1

Freely soluble                                                     From 1 to 10

Soluble                                                              From 10 to 30

Sparingly soluble                                              From 30 to 100

Very slightly soluble                                      From 100 to 1000

Practically insoluble                                      From 1000 to 10,000

Slightly soluble                                                 10,000 and over

The equilibrium solubility is based on the phase-solubility technique  proposed by Higuchi-Connors .

Method

  1. Drug dispersed in solvent in a closed container
  2. agitated at a constant temperature using shakers
  3. samples of the slurry are withdrawn as a function of time
  4. clarified by centrifugation and assayed by HPLC, UV, GC etc

pKa determination

pKa is the dissociation constant of a drug

The un-ionized drug is lipid soluble thus permeates through lipid  membrane.

The ionized substance is lipid insoluble therefore permeation is slow

Degree of ionization depends on pH

 

Determined by uv spectroscopy, potentiometric titration, titrimetric  method

SOLUBILIZATION

“Solubilization is defined as the spontaneous passage of poorly water soluble solute molecules into an aqueous solution of asoap or detergent in which a thermodynamically stable solution is formed”.

➢It is the process by which apparent solubility of an otherwise sparingly soluble substance is increased by the presence of surfactant micelles .

❑ MICELLES: –

➢ The mechanism involves the property of surface active agents to form colloidal aggregates known as micelles.

➢ 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)

General Method of Increasing  the Solubility

➢ Addition of co-solvent

➢ pH change method

➢ Reduction of particle size

➢ Temperature change method

➢ Hydotrophy

➢ Addition of Surfactant

➢ Dielectrical Constant

➢ Complexation

Partition Coefficient

A measurement of drug lipophilicity i,e the ability to cross the cell membrane


Distribution coefficient

The octanol-water system is widely accepted to explain these phenomenon.

Buccal membrane : butanol-pentanol system

Blood-Brain barrier: chloroform-cyclohexane

Determined by SHAKE FLASK METHOD

SHAKE FLASK METHOD

Drug is shaken between octanol and water.

Aliquot is taken and analyzed for drug content

RULE OF FIVE : for drug permeates through passive diffusion

1. Log P is greater than 5

2. Molecular weight >500

3. There are more than 5 hydrogen bond donors (number of NH + OH)

4. There are more than 10 hydrogen bond acceptors (number of hydrogen + oxygen )

5. Molar refractivity should be between 40-130

DISSOLUTION

DISSOLUTION

When Kd << Ka ,dissolution is significantly slower and the absorption is  described as dissolution-rate limited.

The dissolution rate of drug substance in which surface area is constant during dissolution is described by Noyes-Whitney equation.

Constant surface area is obtained by compressing powder into a disc of  known area with a die and punch apparatus.

Hydrodynamic conditions are maintained with Static-disc dissolution  apparatus and Rotating disc apparatus

static dissolution apparatus and rotating disc apparatus

STABILITY ANALYSIS

1. Solution stability

2. Solid state stability

1. SOLUTION STABILITY

▪ The decomposition of drug occurs through hydrolysis, oxidation, photolysis.

➢ Hydrolysis (anaesthetics, vitamins etc )

a) Ester hydrolysis

R’-COOR + H+ + OH- ———-> RCOOH + ROH

   ester                                                 acid       alcohol

b) Amide hydrolysis

RCONHR’ + H+ + OH- ————->  RCOOH + H2N-R’

Amide                                                   Acid          Amine

➢ Oxidation

used to evaluate the stability of pharmaceutical preparations

Eg : steroids, vitamins, antibiotics, epinephrine

Autoxidation

Materials + molecular oxygen

                  homolytic fission

Free radicals are produced.

Oxygen sensitivity is measured by bubbling air through the compound or adding hydrogen peroxide.

➢ Photolysis

pharmaceutical compounds

exposure to uv light

                               absorbs the radiant energy

undergoes degradative reactions

2. SOLID-STATE STABILITY

1o objective: identification of stable storage conditions.

identification of compatible excipients

Solid-state stability depends on the temperature , light, humidity,  polymorphic changes, oxidation.

Solid-State Stability profile of a new compound

Samples are placed in open vials and are exposed directly to a variety of  temperatures, humidities, and light intensities for up to 12 weeks.

Vials exposed to oxygen and nitrogen to study the surface oxidation and  chemical stability , polymorphic changes and discolouration.

Stability data obtained at various humidities may be linearized with respect  to moisture using the following apparent decay rate constant (KH )

k H = [ gpl].k 0

gpl= concentration of water in atmosphere in units of grams of water per liter  of dry air .

ko = decay rate constant at zero relative humidity

Mole fraction of the solid that has liquefied (Fm ) is  directly proportional to its decay rate.

Drug- excipient compatibility

Compatibility test play a very important role in the preformulation studies of oral dosage forms

An incompatibility in the dosage form can result in any of the following  changes:

➢ Changes in organoleptic properties

➢ Changes in dissolution performance

➢ Physical form conversion

➢ An decrease in potency

METHOD

  1. Drug + Excipients (1:1)
  2. Powder samples dispersed into glass ampoules
  3. 1 ampoule  or 1 ampoule (sample + water)
  4. stored at a particular temperature (500 C) and analysed

In emulsions the studies include measuring the critical micelle concentration of the formulations

For oral use preparations compatibility of the ingredients (ethanol,  glycerine, syrup, sucrose, buffers and preservatives)

Also, Visit:

B. Pharma Notes | B. Pharma Notes | Study material Bachelor of Pharmacy pdf

B. Pharma Handwritten Notes

B. Pharma PDF Books

B. Pharma Lab Manual

D. Pharma Lab Manual

B. Pharma 8th Semester Previous Year Question Paper

D. Pharma Notes

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