Physico-chemical Properties Affecting Drug Formulation. Physical and chemical properties of Drug substances

2. Assignment:
• PHARMATECH
TOPIC:
• PHYSICO-CHEMICAL
PROCESSES
Submitted By:
• 01
• 02
• 04
• 12
• 19

3. Submitted to:
Prof. Dr. Sajid Bashir

4. ROLL NUMBER
01
CONTENTS:
o Introduction
o List of Processes
o Crystallinity
o Polymorphism

5. Physicochemical Properties:
• Physical Properties/Processes
( Influence on drug and formulation)
• Chemical Properties/Processes
( Influence on drug and formulation)

6. • Physical and chemical reactions involved in the
formation of or changes in the structure of atoms and
molecules and their interaction affecting the drug
kinetics.
• Investigation of physical and chemical properties of a
drug substance - alone and or when combined with
excipients is crucial during pre-formulation studies.
What are physicochemical properties?

7. Physical Properties:
A. BULK CHARACTERISTIC
 Crystallinity and Polymorphism
 Hygroscopicity
 Particle Size & Surface Area
 Flow properties & Bulk density
 Compressibility
 Drug- Excipient Compatibility

8. B. SOLUBILITY ANALYSIS
 Ionization constant
 Solublization.
 Partition Coefficient
 Thermal effect
 Common ion effect.
 Dissolution.
C. STABILITY ANALYSIS
 Solid State Stability.
 Solution State Stability

9. Chemical Properties /Processes:
 Oxidation.
 Hydrolysis.
 Photolysis.
 Racemization.
 Polymerization.
 Isomerization.
 Decarboxylation.
 Enzyme Decomposition.

10. CRYSTALLINITY & POLYMORPHISM:
CRYSTALLINITY
 Crystal habit (i.e outer appearance of the crystal) and the Internal structure
(i.e molecular arrangement within the solid) can affect physicochemical
property of the drug
Internal structure
Crystalline Amorphous
•Molecules are arranged in 3D
•Prepared by slow precipitation
•Low thermodynamic energy so
low solubility rate
•Molecules are randomly arranged
•Prepared by rapid precipitation
•Higher thermodynamic energy so
higher solubility rate
• Crystal habit and internal structure of a drug can affect bulk and physicochemical properties ,
which range from flow ability to stability

11. Crystal lattice of NaCl
o Sodium chloride crystallizes in a cubic lattice.
o There are 6 Cl surrounding the Na, and 6 Na around each Cl

12. POLYMORPHISM:
 A compound may be amorphous or crystalline, where the compound has more than
one crystalline form it is said to be exhibit polymorphism.
 Polymorphisms generally have :
 Different melting points ,
 X-Ray diffraction patterns and
 Solubility even though they are chemically identical.
 Although a drug substance may exist in two or more polymorphic forms, only one form is
thermodynamically stable at a given temperature and pressure.
 -In general the stable polymorph exhibits the highest melting point, the lowest solubility,
and the maximum chemical stability. -

13. Polymorphism Example
 DIAMOND AND GRAPHITE:

Polymorphism is exhibited in diamonds and graphite. Both diamond and graphite are
polymorphs of the same element carbon.
 Both the elements entirely consist of carbon but they have different crystalline
structures and physical properties, since the structure determines the properties of the
compounds.

14. Structures of Diamond and Graphite

15. Crystal Habit Types

16. Polymorphism in pharmaceuticals Case Studies
 For Medicine administered orally as a crystalline solid, dissolution rates depend on the exact
crystal form of a polymorph
 In a classic patent case the pharmaceutical company GlaxoSmithKline defended its patent
for the polymorph type II of the active ingredient in Zantac against competitors while that of
the polymorph type I had already expired
 In the case of the antiviral drug ritonavir, not only was one polymorph virtually inactive
compared to the alternative crystal form, but the inactive polymorph was subsequently
found to convert the active polymorph into the inactive form on contact, due to its lower
energy and greater stability

17.  Paracetamol powder has poor compression properties; this poses difficulty in making tablets, so a
new polymorph of paracetamol was found which is more compressible
 Due to differences in solubility of polymorphs, one polymorph may be more active therapeutically
than another polymorph of same drug.
 Cortisone acetate exists in at least five different polymorphs, four of which are unstable in water
and change to a stable form.
 Estrogen and chloroamphenicol also show polymorphism.

18. • With respect to the hydrogen bonds formed by the carboxylic acid groups both
polymorphs form identical dimer structures.
• In form I two salicyl molecules form centrosymmetric dimers through the acetyl groups
with the (acidic) methyl proton to carbonyl hydrogen bonds
• In the newly discovered form II each salicyl molecule forms the same hydrogen bonds but
then with two neighboring molecules instead of one.
o Polymorphism is also established for ASPIRIN
• A new crystal type was found following attempt to co-crystallization of
aspirin and levetiracetam from hot acetonitrile.
• Form II is only stable at 100 K and reverts to from I at ambient temperature.

19. ROLL NUMBER
02
CONTENTS
o Hygroscopicity
o Particle Size
o Particle Surface Area

20. HYGROSCOPICITY
Hygroscopicity: -
It is the tendency of material to absorb moisture from atmosphere & be dynamic equilibrium
with water in the atmosphere.
Deliquescent: -
It is the hygroscopic substance which absorb moisture from air and they can be liquefied by
partially or wholly forming solution.
Efflorescent: -
A substance which loses water to form a lower hydrate or become anhydrous is termed as
efflorescent

21.  Some drugs have the tendency to adsorb atmospheric moisture
 Now the amount of adsorbed moisture depends upon the
 atmospheric humidity,
 temperature,
 surface area and
 the mechanism for the moisture uptake
 The change in moisture level greatly influences chemical
 Stability,
 Flowability,
 Compactability.

22. List of examples:
Hygroscopic & Deliquescent Efflorescent
Ephedrine atropine
Hyoscymine cocaine
Phenobarbital codeine
Pilocarpine scopolamine
Physostigmine caffeine
Glycerinated gelatin & PEG base of suppository are hygroscopic in nature

23. METHOD OF DETERMINATION
To carry out study, sample of compound are accurately weighed into container and placed at various humid
condition for period of upto 2 weeks.
If Weight gain – Deliquescent or Hygroscopic
If Weight loss – Efflorescent
EFFECTS OF HYGROSCOPCITY:
• It affects the flow property.
• It affects compression characteristic , granulation & hardness of final tablet.
• It also affects compaction.
• Important in aerosol.
• Affects chemical stability of hydrolysable drug.

24. PARTICAL SIZE AND SURFACE AREA:
PARTICLE SIZE:
o It affects the bulk flow, formulation homogeneity of the drug particles
o Various chemical and physical properties of drug substances are affected by their particle size
distribution and shapes The effect is not only on the physical properties of solid drugs but also , on their
biopharmaceutical behavior .
o In case of tablets, size and shape influence the flow and the mixing efficiency of powders and granules.
o Size can also be a factor in stability .
o Fine materials are relatively more open to attack from atmospheric oxygen, the humidity, and
interacting excipient than are coarse materials.

25.  Particle size and shape can be determined by using
• optical microscope ,
• polarizing microscope or
• by scanning electron microscope (SEM)
• Transmitted X-Ray beam
 The data recorded either by a sketch or more accurately by a photomicrograph .
 Polarizing microscope is used to determine whether a compound is crystalline or amorphous .
 Crystalline structures are visible (Refract the polarized light). Amorphous are invisible
.
General techniques for determining particle size:

26. Microscopy
o Most rapid technique.
o But for quantitative size determination requires counting large number of particles.
o Suspending the material in non dissolving fluid (water or mineral oil)
X-RAY DIFFRACTION TECHNIQUE

27. Surface Area:
 Particle size and surface area of a solid drug are inversely related.
 Two types of surface area of interest are:
 Absolute surface area
 Effective surface area
• Absolute surface area which is the total area of solid surface of any particle.
• Effective surface area which is the area of solid surface exposed to the dissolution medium.
 HOW TO OVERCOME THE EFFECTS TO INCEREASE EFFECTIVE SURFACE AREA:
 Use of surfactant as a wetting agent
• Decreases the interfacial tension
• Displaces the adsorbed air with the solvent
• Eg: polysorbate 80 increases the bioavailability of phenacetin by promoting wettability

28. Effects of particle size:
• On Chemical and physical properties of drug substances.
• Bioavailability of drug substances(Griseofulvin,Chlorpropamide).
• Flow and mixing efficiency of powders and granules in making tablets.
• Fine materials relatively more open to attack from atmospheric O2, heat, light, humidity, and interacting
excipients than coarse materials.
• Very fine materials are difficult to handle, overcome by creating solid solution in a carrier (water-
soluble polymer).
•
• Important to decide, maintain, and control a desired size range.

29. Effect of surface area:
o The greater the concentration of colloidal particles, the greater is the particle surface area of
the system and, hence, the ability to “react” with its environment. Further, as particle size is
reduced, the internal surface becomes exposed and with it a potential change in the number
and/or type of surface chemical sites and groups
Processes that may be affected by surface area include the following:
• Aggregation/ deaggregation of particles during blending
• Flowability of drug, excipients and mixed powder
• Amount of granulating liquid required to avoid either overmassing or undermassing
• Compactability of powder or granulation
• Hygroscopicity of powder or powder mix

30. ROLL NUMBER
04
CONTENTS
Ionization constant
Partition co efficient
Solubililization
Stability analysis Into

31. Ionization constant:
 A constant that depends upon the equilibrium between the ions and the molecules that are
not ionized in a solution or liquid—symbol K; also called dissociation constant
o Determination of the dissociation constant for a drug capable of ionization within a pH range of 1 to
10 is important since solubility and consequently absorption, can be altered by orders of magnitude
with changing pH.
o The Henderson – Hasselbalch equation provides an estimate of the ionized and un ionized drug
concentration at a particular pH.
 For acidic compounds
pH= pKa + log(ionized drug)/(un ionized drug)
 For basic compounds
pH = pKa + log (un-ionized drug]) / [ionized drug])

32. Methods to determine pKa:
 Potentiometric method
 Conductivity method
 Dissolution rate method
 Liquid -liquid partition method
 Spectrophotometric method
Uses of this equation
To determine pKa.
To predict solubility of any pH provided that intrensic solubility(Co) & pKa are known
To facilitate the selection of suitable salt forming compounds
To predict the solubility and pH properties of the salt
a

33. Solubilization:
o Solubilization is the process of incorporating the solubilizate (the component that
undergoes solublization) into or onto the micelles.
Many different approaches have been developed to improve drug solubility
Micronization:-
E.g. Griseofulvin shows increased solubility by reducing particle size
Change in pH:-
E.g. Solubility of Nimesulide increases as pH is increased
E.g. Arginine increases solubility of coumarin.
 Cosolvency
 Addition of a water miscible solvent can often improve the solubility of a weak electrolyte or non-
polar compound in water by altering the polarity of the solvent
 Limited choice due to possible toxicity & irritancy.
 Water / ethanol : most widely used system

34. Complexation:-
Eg. The complexation of iodine with 10-15% pvp can improve aq. Solubility of active agent
Use of metastable polymorphs:-
Eg. B form of chloramphenicol palmitate is more water soluble than A & C forms.
Solubilization by surfactant:-
o Eg. Gelucire 44/14 is a surface active excepient that can solubilize poorly soluble drug.
o Eg. Anionic and cationic surfactant exhibit drramatically higher solubilization of gliclazide,
while nonionic surfactant showed significantly lower solubilizing ability.
Schematic diagram of micellar solubilization of fatty substance in water with the use of a
dispersant.

35. Partition Coefficient:
o Partition Coefficient (oil/ water) is a measure of a drug’s Lipophillicity and an indication of its
ability to cross cell membranes.
o It is defined as the ratio of unionized drug distributed between the organic and aqueous phases at
equilibrium.
o P o/w = (C oil / C water) equilibrium.
o In formulation development, the n-octanol/water partition coefficient is commonly used
p= (Concentration of drug in octanol)
(Concentration of drug in water)------ For unionizable drug
p= (Concentration of drug in octanol)
(1-alpha) (Conc of drug in water)----- For ionizable drug
 p>1 – lipophillic drug
 P<1 – Hydrophillic drug

36. Methods to determine P:-
 Shake flask method
 Chromatographic method (TLC, HPTLC)
 Counter current and filter probe method
Applications of P:-
 Measure of lipophillic character of molecule
 Recovery of antibiotics from fermentation broth
 Extraction of dosage from biological fluid
 Absorption of drug from dosage form
 Study of distribution of flavoring oil between oil & water in emulsion

37. Effects of partition coefficient:
• Partition coefficient influence permeation of a drug across biological membrane.
• Following administration the drug must travel through a variety of membranes to gain
acess to the target area.
• Drugs with extremely high partition co-efficient (very oil-soluble) readily penetrate the
membranes.
• While drugs with exessive aqueous water solubility can not penetrate the membranes.
.

38. STABILITY ANALYSIS:
 Stability of pharmaceutical product may be defined as the capability of a particular
formulation in a specific container/closure system to remain within its physical, chemical,
microbiological therapeutic and toxicological specification.
 Extent to which a product retains within specified limits” and throughout its period of storage
and use(i.e its shelf life) the same properties and characteristics that it possessed at the time
of its manufacturer (USP)
 The stability of the drug substance is first assessed in the pre formulation stage.
 Stability/ compatibility with various solvents, buffered, solutions, and excipients considered
for formulation developments

39.  There are five types of stability that must be consider for each drug

40. Roll Number
12
CONTENTS
o Types of Stability
o Chemical Characteristics
o Oxidation
o Hydrolysis

41.  TWO types of stability studies:
1. Solid Phase stability studies
2. Liquid Phase stability studies
Solid phase stability:-
o It includes both physical and chemical stability
o Physical changes caused by Polymorphic transitions and Hygroscopicity.
o Chemical changes such as solvolysis, oxidation, photolysis, pyrolysis.
o Examples
• Amorphous materials are less stable than their crystalline counterparts.
• Above 65% relative humidity the beta form of chlortetracycline hydrochloride transforms
into alpha form.

42. Solution phase stability:
o This study assures that the drug substance does not degrade when exposed to
gastrointestinal fluids.
o The effect of pH on stability is important in the development of both oral and Parenteral
dosage forms
o Example: Acid sensitive drugs protected from highly acidic environment of the
stomach by coating it with suitable polymers.

43. Techniques for solid state stabilities:
o Solid state NMR Spectroscopy (SSNMR)
o Powder x-ray diffraction (PXRD)
o Fourier transform IR (FTIR)
o Raman Spectroscopy
o Differential scanning calorimetry (DSC)
o Thermo gravimetric analysis (TGA)
o Dynamic vapour sorption (DSV)
- The primary objective is identification of conditions necessary to form a stable drug product.
These studies include the effects of:
o -pH -Oxygen
o -Light -Temperature
o -Ionic strength -Co solvent

44. Chemical Characteristics:
Oxidation:
It is very common pathway for drug degradation in both liquid and solid formulation.
 Oxidation is the gain of oxygen, loss of hydrogen and/or loss of electrons
When iron reacts with oxygen it forms a chemical called rust. The iron is oxidized and the
oxygen is reduced.
 Oxidation occurs in two ways
 Auto oxidation
 Free radical oxidation

45. Functional group having high susceptibility towards oxidation:-
 Substituted aromatic group (Toluene, Phenols, Anisole).
 Alkenes
 Ethers
 Thioethers
 Amines
Commonly viewed example of oxidation
in daily life

46. FACTORS AFFECTING OXIDATION PROCESS
1) Oxygen concentration
2) Light
3) Heavy metals particularly those having two or more valence state
4) Hydrogen & Hydroxyl Ion
5) Temperature
PREVENTION OF OXIDATION
1) Reducing oxygen content
2) Storage in a dark and cool condition
3) Addition of chelating agent (Eg. EDTA, Citric acid, Tartaric acid)
4) Adjustment of pH
5) Changing solvent (Eg. Aldehydes, ethers, Ketones, may influence free radical reaction)
6) Addition of an antioxidant or reducing agent (e.g. H2, CO, Zn etc.).

47. HYDROLYSIS
o It is the cleavage of chemical bonds by the addition of water.
o The reaction of water with another chemical compound to form two or more products, involving
ionization of the water molecule usually splitting the other compound.
Examples include :
o the catalytic conversion of starch to glucose,
o saponification, and
o the formation of acids or bases from dissolved ions.
When this attack is by a solvent other than water than it is known as solvolysis

48. Conditions that catalysis the breakdown
•Presence of hydroxyl ion
•Presence of hydride ion
•Presence of divalent ion
•Heat
•Light
•Ionic hydrolysis
•Solution polarity and ionic strength
•High drug concentration

49. PREVENTION OF HYDROLYSIS:
pH adjustment
o Formulate the drug solution close to its pH of optimum sability.
o Addition of water miscible solvent in formulation
o Optimum buffer concentration
Addition of surfactant
o Nonionic, cationic, and anionic surfactant stabilizes the drug against base catalysis
Salts and Esters Eg. Phosphate esters of clindamycine
o The solubility of pharmaceuticals undergoing ester hydrolysis can be reduced by forming less soluble salts.
o By use of complexing agent

50. ROLL NUMBER
19
CONTENTS
o Photolysis
o Racemization
o Poly/Isomerization
o Decarboxylation
o Complexation

51. PHOTOLYSIS:
 Photo dissociation, photolysis, or photodecomposition is a chemical reaction in which
a chemical compound is broken down by photons.
 Since a photon's energy is inversely proportional to its wavelength, electromagnetic waves
with the energy of visible light or higher, such as ultra violet , X-rays and gamma rays are
usually involved in such reactions.

52. PHOTODECOMPOSITION PATHWAY
o N-Dealkylation
E.g. Di-phenylhydramine , Chloroquine, Methotrexate
o Dehalogination
E.g. Chlorpropamide, Furosemide
o Dehydrogenation of Ca++channel blocker
E.g. Solution of Nifedipine
o Oxidation
Eg. Chlorpromazine & other Phenothiazines give N- & S- oxides in the presence of sunlight

53. PREVENTION OF PHOTODECOMPOSITION
o Suitable packing.
Eg. Yellow-green glass gives the best protection in U.V. region while Amber gives considerable
protection against U.V. radiation but little from I.R.
o Protection of drug from light
Eg. Nifedipine is manufactured under Na light.
o Avoiding sunbath.

54. RACEMIZATION
 Racemization is the process in which one enantiomer of a compound, such as an L-amino acid,
converts to the other enantiomer.
 The compound then alternates between each form while the ratio between the (+) and (–) groups
approaches 1:1, at which point it becomes optically inactive.
 If the racemization results in a mixture where the enantiomers are present in equal quantities, the
resulting sample is described as racemeric or a racemate.

55.  The inter-conversion from one isomer to another can lead to
o different pharmacokinetic properties (ADME) as well as
o different pharmacological &
o toxicological effect.
 Example: L-epinephrine is 15 to 20 times more active than D-form, while activity of
racemic mixture is just one half of the L-form.
 It depends on
o temperature,
o solvent,
o catalyst &
o presence or absence of light

56. Biological significance:
• Many psychotropic drugs show differing activity or efficacy between isomers,
e.g. Amphetamine is often dispensed as racemic salts while the more active dextro-
amphetamine is reserved for severe indications;
• Another example is Methadone, of which one isomer has activity as an opioid agonist
and the other as an NMDA antagonist.

57. POLYMERIZATION
 Polymerization is a process of reacting monomer molecules together in a chemical reaction
to form polymer chains or three-dimensional networks.
 It is a continuous reaction between molecules.
 More than one monomer reacts to form a polymer.
 Eg. Darkening of glucose solution is due to polymerization of breakdown product [5-
(hydroxyl methyl) furfural.(a colorless liquid used in synthetic resin manufacture).
 Eg. Shellac on aging undergoes polymerization & hence prolongs disintegration time &
dissolution time.

58. ISOMERIZATON
 Is the process by which one molecule is transformed into another molecule which has exactly the
same atoms, but the atoms have a different arrangement e.g. A-B-C → B-A-C (these related
molecules are known as isomers).
Examples:-
o Tetracycline & its derivatives can undergo reversible Isomerization at pH range 2-6.
o Trans-cis Isomerization of Amphotericin B.

59. Significance:
Isomerism finds its importance in the field of clinical pharmacology and
pharmacotherapeutics, as isomers differ in their pharmacokinetic and pharmacodyanmic
properties.
• Cetrizine to levocetrizine is one of such examples, where effective and safer drug has been
made available.
• .Levocetrizine has smaller volume of distribution than its dextroisomer.
• Esomeprazole is more bioavailable than racemic omeprazole;
Familiar isomers

60. DECARBOXYLATION
 Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon
dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a
carbon atom from a carbon chain.
E.g. Solid p-amino salicylate undergoes decarboxlation to m- aminophenol & Carbon dioxide.

62. COMPLEXATION:
o A complex is an entity formed when two molecules , such as a drug and a solubilizing agent
(ligand) are held together by weak forces .
o For complex formation to occur , drug and ligand molecules should be able to donate or accept a pair
of electrons .
• Vitamin K
• Caffeine
• Benzoic acid
• Cholesterol
• PEG
• PVP
• b-cyclodextrin
Example…………………..
Complex formation between the drug benzocaine and ligand caffeine can be attributed to the dipole- dipole
interaction between a partial negative charge on carboxy oxygen of benzocaine and a partial positive charge on
nitrogen of caffeine.. EXAMPLES

63. REFERENCES:
o The Science & Practice of Pharmacy by Remington. (19th edition):
o Physical Pharmacy by Martin
o Biopharmaceutics by Leon Shargel
o Wikipedia-Free encyclopedia
o Dosage Form and Design by Ansel