PREFORMULATION NSU (Final).ppt

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DR. Mohammad Shariare

PREFORMULATION

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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.

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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.

 _{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 :}

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GOALS OF PREFORMULATION

 _{To establish the necessary physicochemical parameters of}

new drug substances.

 _{To determine kinetic rate profile.}

 _{To establish physical characteristics.}

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Preliminary Evaluation

a) Compound identity.

b) Formula and molecular weight.

c) Structure.

d) Therapeutic indications:

- Probable human dose. - Desired dosage form(s)

- Bioavailability model - Competitive products

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Preformulation Characterization

 _{Spectroscopy – simple UV assay}  _{Solubility – phase solubility purity}

 _{Melting point – DSC – polymorphism, hydrates, solvates}  _{Assay development – UV, TLC, HPLC}

 _{Stability – thermal, hydrolysis, oxidation, photolysis, metal ions,}

pH

 _{Microscopy – morphology, particle size}

 _{Powder flow (bulk density, angle of repose) – tablet and capsule}

formulation

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ORGANOLEPTIC PROPERTIES

COLOR ODOUR TASTE

OFF-WHITE PUNGENT ACIDIC

CREAM-YELLOW SULFUROUS BITTER

SHINY FRUITY SWEET

AROMATIC TASTELESS

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COLOR

 _{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}

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Odour

 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:-

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

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PURITY

 _{Designed to estimate the levels of all known &}

significant impurities & contaminates 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

 _{Techniques used for purity determination –}

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PARTICLE SIZE

 _{Particle size is characterized using these terms :}

i.

Very coarse

ii.

Coarse

iii.

Moderately coarse

iv.

Fine

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PARTICLE SIZE



Particle size can influence variety of

important factors :

- Dissolution rate

- Suspendability

- Uniform distribution

- Penetrability

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Methods to Determine Particle Size



_Sieving



Microscopy



Sedimentation rate method



Light energy diffraction



Laser holography

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Methods to Determine Particle Size

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.}

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Methods to Determine Particle Size

3. Sedimentation method :

 Range : 1 - 200 µm

 _{Andreasen pipette is used.}

 _{Particle size is calculated by stoke’s law :}

d_st=

Where,

h = distance of fall in time, t n_o = viscosity of the medium ρ_s = density of the particles

ρ₀ = density of the dispersion medium g = acceleration due to gravity

18 η₀h

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Methods to Determine Particle Size

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}

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Methods to Determine Particle Size

6. Cascade impaction :

 _{The principle that a particle driven by an airstream will}

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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.}

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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

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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}

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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

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PARTICLE SHAPE

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PARTICLE SHAPE

 Particle shape will influence the surface area, flow of

particles, packing & compaction properties of the particles.

 A sphere has minimum surface area per unit volume.

 Therefore, these properties can be compared for

spheres & asymmetric particles, in order to decide the shape.

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SURFACE AREA

 _{Particle 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}

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Methods for determining

surface area

1. Adsorption method :

 Particles with a large specific surface are

good adsorbents for the adsorption of gases & of solutes from solution.

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HOWEVER SIZE REDUCTION

IS NOT REQUIRED IN FOLLOWING CASES

 _{WHEN DRUG IS UNSTABLE.}

 _{DEGRADE IN SOLUTION FORM.}

 _{PRODUCE UNDESIRABLE EFFECTS.}

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“

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 ”.

Solubilization

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 _{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.

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Step2: Molecules of the solid breaks away from the bulk

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 _{If solubility is <1mg/ml indicates need for salt}

formation to improve solubility.

_{If solubility is <1mg/ml in pH= 1 to 7,}

preformulation study should be initiated.

 Solubility should ideally be measured at two temperatures: 4°C and 37°C.

_{4°C to ensure Physical stability.}

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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

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Determination of solubility

 The following points should be considered

 The solvent & solute must be pure.

 A saturated solution must be obtained before any

solution is removed for analysis.

 The method of separating a sample of saturated

solution from undissolved solute must be satisfactory.

 The method of analyzing solution must be reliable

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Solubility Determination Method

_{Solubility is normally depends on temperature,}

so temperature is recorded in each solubility measurement.

_{Plot of solubility against temperature is}

commonly used for solubility determination.

_{Two methods are available for determination}

are as follow.

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_{Analytic method that are particularly useful}

for solubility measurement include HPLC, UV spectroscopy, Fluorescence spectroscopy and Gas chromatography.

_{Reverse phase HPLC offer accurate and}

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_{Addition of co-solvent} _{pH change method}

_{Reduction of particle size}

_{Temperature change method} _{Addition of Surfactant}

 Dielectrical Constant

_Complexation

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Ionization constant (pKa)

Can be calculated by Henderson Hasselbach

For acidic drugs….pH= pKa+ log [ionized drug] [unionized drug]

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pH Solubility Profile

 _{The solubility of acidic or basic drug will show}

difference in solubility with changes in pH.

_{pH solubility profile of a drug can be established}

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Partition Coefficient

 _{It is the ratio of unionized drug distributed}

between organic and aqueous phase at equilibrium.

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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}

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Crystallinity

 _{Change with internal structure usually alters}

crystal habit.

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Different shapes of crystals

 _{Cubic or isometric}_{- not}

always cube shaped. Also find as octahedrons (eight faces) and dodecahedrons (10 faces).

 _Tetragonal_{- similar to cubic}

crystals, but longer along one axis than the other, forming double pyramids and prisms.

 _Orthorhombic_{- like}

tetragonal crystals except not square in cross section

(when viewing the crystal on end), forming rhombic

prisms or dipyramids (two pyramids stuck together).

 _Hexagonal_{- six-sided}

prisms. When you look at the crystal on-end, the cross section is a hexagon.

 _Trigonal_{- possess a single}

3-fold axis of rotation

instead of the 6-fold axis of the hexagonal division.

 _Triclinic_{- usually not}

symmetrical from one side to the other, which can lead to some fairly strange shapes.

 _Monoclinic_{- like skewed}

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Different types of Solid

 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

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 _{Solubility & dissolution rate are greater for}

amorphous form then crystalline, as amorphous form has higher thermodynamic energy.

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

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Melting Point

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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}

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Polymorphism

 _{The polymorph which can be changed from one}

form into another by varying temp. or pressure is called as Enantiotropic polymorph.

Eg. Sulfur.

 _{One polymorph which is unstable at all temp. &}

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Polymorphism

 _{Polymorph differ from each other with respect to}

their physical property such as Solubility

Melting point Density

Hardness

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Polymorphism

 During preformulation it is important to identify

the polymorph that is stable at room temp.

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

preferable.

2)Riboflavin has I,II & III forms, the III form shows 20 times more water solubility than

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Techniques for studies of crystals

 _Microscopy

 _{Hot stage microscopy}  _{Thermal analysis}

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Why 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

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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}

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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}

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Forced degradation studies

 _{Acidic & Basic conditions.}

 _{Dry heat exposure}

 _{UV radiation exposure}

 _{Influence of pH}

 _{Influence of temperature}

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Chemical degradation studies

 Hydrolysis

 _Oxidation

 _Reduction

 Decarboxylation

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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}

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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

􀂄 Selection of samples

• API, excipient, batches 􀂄 Scope

• Appearance

• Appropriate physical-chemical parameter • Assay / Degradation products

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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}

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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}

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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}

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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

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Climatic Zones / Storage conditions

Climatic Zone Countries

Calculated data

Temp. MKT humidity

°C °C % r.h.

Derived data

Temp humidity

°C % r.h.

Climatic Zone I "Temperate"

Japan, United Kingdom, Northern Europe,

Canada, Russia, United States

20 20 42 21 45

Climatic Zone II "Mediterranean, Subtropical"

Japan, United States, Southern Europe

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Climatic Zones / Storage conditions

Climatic Zone Countries

Calculated data

Temp. MKT humidity

°C °C % r.h.

Derived data

Temp humidity

°C % r.h.

Climatic Zone III "Hot, dry"

Iran, Iraq, Sudan 26,4 27,9 35 30 35

Climatic Zone IV "Hot, humid"

Brazil, Ghana, Indonesia, Nicaragua,

Philippines

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 _{Prof. Dr. Basavaraj K. Nanjwade}_{M. Pharm.,}

Ph.D, Department of Pharmaceutics, KLE University College of Pharmacy, Karnataka, India.