University of Sulaimani College of Pharmacy Dept. of ... · • Preformulation is a phase of the research and development process where the scientist characterizes the physical, chemical

University of Sulaimani College of Pharmacy

Dept. of Pharmaceutics5th stage – First Semester

Preformulations I Industrial Pharmacy I, Dr. rer nat Rebaz Ali 1


Outlines

• Introduction

• Bulk characterization

• Crystallinity and polymorphism

• Hygroscopicity

• Fine particle characterization

• Bulk density

• Powder flow properties

• Solubility analysis

• Stability analysis


Introduction

• Preformulation is a phase of the research and development process where

the scientist characterizes the physical, chemical and mechanical properties

of a new drug substance.

• Preformulation involves a full understanding of the physicochemical

properties of drugs and other ingredients (excipients) in a dosage form and

how they may interact.


Introduction cont.

• Objective

• The preformulation investigations confirm that there are no significant

barriers to the compound’s development as a marketed drug.


Introduction cont.


Introduction cont.


Preformulation research area

Stability analysis

- Stability in toxicological formulation

- Solution stability

- Solid state stability

Solubility analysis

- Ionization constant pKa

- pH solubility profile

- Common ion effect Ksp

- Thermal effect

- Solubilization

- Partition coefficient

- Dissolution

Bulk characterization

- Crystallinity and polymorphism

- Hygroscopicity

- Fine particle characterization

- Bulk density

- Powder flow properties

Preformulation research area


Outlines

• Introduction



• Hygroscopicity


• Bulk density





Crystallinity and polymorphism

Chemical compound

Habit Internal str.

Amorphous Crystal

Single entry

Polymorphs

Molecular adduct

Solvate (hydrate)

Inclusion compound

Cage (clathrate) Layer Channel


Crystallinity and polymorphism cont.

• Crystal habit and the internal structure of drug can affect bulk and

physicochemical properties, like flowability and chemical stability.

• Habit is the description of the outer appearance of a crystal.

• The internal structure is the

molecular arrangement within the

solid.

• In crystals atoms or molecules are

arranged in highly ordered form

and is associated with three-

dimensional periodicity.

• The repeating three-dimensional

patterns are called crystal lattices

Crystals


Crystalline vs amorphous

Crystalline forms Amorphous forms

(i) Crystalline forms have fixed internal

structure

(ii) The true density is higher.

(iii) They are more stable.

(iv) They have lesser solubility.

(v) They have lesser tendency to change

its form during storage.

(vi) They have melting points

(i) Amorphous forms do not have any

fixed internal structure

(ii) The true density is lower.

(iii) They are less stable.

(iv) They have greater solubility.

(v) They tend to revert to more stable

forms during storage.

(vi) They have a glass transition

temperature.



Chemical compound

Habit Internal str.

Amorphous Crystal

Single entry

Polymorphs

Molecular adduct

Solvate (hydrate)

Inclusion compound


What is pseudopolymorphism?


Polymorphism

• Polymorphism is ability of a compound to crystallize as more than one

distinct crystalline species with different internal lattices.

• Chemical stability and solubility changes due to polymorphism can have an

impact on a drugs bioavailability.

• Many physicochemical properties vary with the internal structure of the

solid drugs, including melting point, density, hardness, crystal shape, and

vapor pressure.

• The highest-melting species is generally stable.

• High melting point = strong lattice = hard to remove a molecule = low

dissolution rate


Polymorphism cont.

• Barbiturates, steroids, and sulphonamides exhibit polymorphism.

• What is pseudopolymophism?

Comparison of mean blood serum level after theadministration of chloramphenicol palmitatesuspensions using varying ratios of the stable (α) andthe metastable (β) polymorphs. M 100% α; N, 25:75β:α; O, 50:50 β:α; P, 75:25 β: α; and L 100% β.


A. Non-Stoichiometric inclusion compounds (or adducts)

• In these crystals, solvent molecules are entrapped within the crystal lattice

and the number of solvent molecules are not included in stoichiometric

number.

1. Channel: When the crystal contains continuous channels in which the solvent

molecule can be included. e.g . Urea forms channel.

2. Layers:- Here solvent molecules are entrapped in between layers of crystals.

3. Clathrates (Cage):- Solvent molecules are entrapped within the cavity of the

crystal from all sides.




Chemical compound

Habit Internal str.

Amorphous Crystal

Single entry

Polymorphs

Molecular adduct

Solvate (hydrate)

Inclusion compound



B. Stoichiometric inclusion compounds

• Solvate, is a molecular complex that has incorporated the solvent molecules

into specific sites within the crystal lattice.

• When the incorporated solvent is water, the complex is called a hydrate.

• Aqueous solubility of hydrous is usually less

than their anhydrous forms.

• The more soluble anhydrous form of

ampicillin produced higher and earlier

peaks in the blood serum levels than the

less soluble trihydrate form.



Analytical methods

Methods Material required per sample

MicroscopyDSC / DTAInfrared spectroscopy X-ray powder diffraction Scanning electron microscopy Thermogravimetic analysisDissolution/solubility analysis

1 mg2-5 mg2-20 mg500 mg2 mg10 mgmg to g

• Analytical methods for characterization of solid


Analytical methods

• Thermal analysis

• Differential scanning calorimetry (DSC) and differential thermal analysis

(DTA) measure the heat loss or gain resulting from physical or chemical

changes within a sample as a function of temperature.

• Examples of endothermic (heat-absorbing) processes are, boiling,

sublimation, vaporization, and chemical degradation.

• Crystallization are usually exothermic processes.


DSC

DSCEndotherm e.g. melting

Exotherm e.g. crystallizationStartup transient

Baseline shift (Tg)


Analytical methods

• Application

• To determine the purity of a sample

• To determine the number of polymorphs

• To determine the thermal degradation of a drug or excipients.

• To determine the glass-transition temperature (Tg) of a polymer

DSC, Carbamazepine form III


Thermogravimetric analysis (TGA)

• TGA measures changes in sample

weight as a function of time or

temperature.

• Desolvation and decomposition

processes are frequently monitored

by TGA.

Anhydrous form

Anhydrous:dihydrate

Dihydrate form

Anhydrous form

Anhydrous:dihydrate 10:1

Dihydrate form


Outlines

• Introduction



• Hygroscopicity


• Bulk density





Hygroscopicity

• Water-soluble salt forms, have a tendency to adsorb atmospheric moisture.

• Moisture content can depend upon the atmospheric humidity, temperature,

and surface area exposure.

• Deliquescent materials adsorb sufficient water to dissolve completely, like

sodium hydroxide on a humid day.

• With most hygroscopic materials, changes in moisture level can greatly

influence many important parameters, such as

• Chemical stability

• Flowability

• CompatibilityAir

Solid particles

Hygroscopic water

Capillary water


• Hygroscopicity tests

• For the purpose of ‘handling’ data points from 0 to 24 hours are taken

• For the purpose of ‘storage’ data points from 0 to 12 weeks are taken.

• Significance of hygroscopicity test

• To decide special handling procedure

• The storage condition i.e. at low humidity environment.

• Special packaging e.g. with desiccant

Hygroscopicity cont.

desiccator

shallow container

saturated saltsolution

powder sample

Fig. 7


Outlines

• Introduction



• Hygroscopicity


• Bulk density





Fine particle characterization

• Parameters those are measured:

• Particle size and size-distribution

• Surface area

• Surface morphology of the particles

• Bulk flow, formulation homogeneity, and dissolution are directly affected by

size, shape, and surface morphology of the drug particles.

• Instrumental methods of particle size characterization

A. Light microscope

B. Sieve analysis


Determination of specific surface area

• Brunauer, Emmett and Teller (BET) nitrogen adsorption method

• A layer of nitrogen molecules is adsorbed to the sample surface at –

196°C

• Once the surface is saturated, the sample is heated to room

temperature, the nitrogen gas is desorbed

• Each N2 molecule occupies an area of 16 A2


Characterization of surface morphology

• Scanning electron microscopy SEM.

• It is a microscope that produces an image by using an electron beam instead

of light that scans the surface of a specimen inside a vacuum chamber.


SEM

• Used to study topography crystallography


SEM

• Coating of samples is required in the field of electron microscopy to enable

or improve the imaging of samples.

• Samples are made conductive by coating with a very thin layer of gold by a

machine called sputter-coater.


Outlines

• Introduction



• Hygroscopicity


• Powder density





Powder density

• Apparent bulk density is determined by pouring preserved (40 mesh) bulk

drug into a graduated cylinder and measuring the volume and weight as it

is.

• Tapped density is determined by placing a

graduated cylinder containing a known mass on a

mechanical tapper apparatus, which is operated

for a fixed number of taps (1000).

VolumeBulk

powder the of WeightDensityBulk Apparent =

volumeTapped

powdertheofWeightdensity Tapped =


Powder density cont.

• Knowing the anticipated dose and tapped formulation density, this figure

could be use to determine the appropriate size for a capsule formulation.

1.4

1.2

1.0

0.8

0.6

0.4

0.2

000

00

0

1

2345

0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1

600 mg

400 mg

200 mg

cap

sule

vo

lum

e m

L

Cap

sule

siz

e

Packed density g/mL



• Particle density is defined as the ratio of particle mass to the particle volume,

including the pores within the particle, but still excluding the gaps between

particles.

• Particle density is measured by the mercury intrusion method.

• Solvents of varying densities could be used to measure true density of the

powder as well!

• Benzene, water and CCl4 could be used

A pycnometer is a typical apparatus for the liquid replacement method



• True density refers to the ratio of the mass of the particle to its actual volume,

excluding pore volume and the volume of the gap between particles.

• True density is determined with helium pycnometer.

• If a powder is compacted into tablets using high pressure, the resultant density

is very close to the true density



• Porosity refers to the ratio of the volume of the pore interior and the space

between particles to the total volume of the powder.

• For tablets with higher porosity, water can penetrate the tablets, more readily

resulting in a faster disintegration time.

Porosity = 1 −𝑏𝑢𝑙𝑘 𝑑𝑒𝑛𝑠𝑖𝑡𝑦

𝑡𝑟𝑢𝑒 𝑑𝑒𝑛𝑠𝑖𝑡𝑦


Thank you for your attention!

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University of Sulaimani College of Pharmacy Dept. of ... · • Preformulation is a phase of the research and development process where the scientist characterizes the physical, chemical