Assignment:

• PHARMATECH

TOPIC:• PHYSICO-CHEMICAL

PROCESSES

Submitted By:

• 01• 02• 04• 12• 19

Submitted to:

Prof. Dr. Sajid Bashir

ROLL NUMBER

01CONTENTS:

o Introductiono List of Processeso Crystallinityo Polymorphism

Physicochemical Properties:• Physical Properties/Processes

( Influence on drug and formulation)

• Chemical Properties/Processes

( Influence on drug and formulation)

• 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?

Physical Properties:

A. BULK CHARACTERISTIC Crystallinity and Polymorphism

Hygroscopicity Particle Size & Surface Area Flow properties & Bulk density Compressibility Drug- Excipient Compatibility

B. SOLUBILITY ANALYSIS Ionization constant Solublization. Partition Coefficient Thermal effect Common ion effect. Dissolution.

C. STABILITY ANALYSIS Solid State Stability. Solution State Stability

Chemical Properties /Processes:

Oxidation.

Hydrolysis.

Photolysis.

Racemization.

Polymerization.

Isomerization.

Decarboxylation.

Enzyme Decomposition.

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

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

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. -

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. 

Structures of Diamond and Graphite

Crystal Habit Types

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

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.

• 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.

ROLL NUMBER

02CONTENTS

o Hygroscopicityo Particle Sizeo Particle Surface Area

HYGROSCOPICITYHygroscopicity: - 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

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.

List of examples:

Hygroscopic & Deliquescent EfflorescentEphedrine atropineHyoscymine cocaine Phenobarbital codeine Pilocarpine scopolaminePhysostigmine caffeine

Glycerinated gelatin & PEG base of suppository are hygroscopic in nature

METHOD OF DETERMINATIONTo 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.

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.

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:

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

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

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.

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

ROLL NUMBER

04CONTENTS

Ionization constantPartition co efficient

SolubililizationStability analysis Into

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])

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 knownTo facilitate the selection of suitable salt forming compoundsTo predict the solubility and pH properties of the salt

a

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

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.

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

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

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.

.

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

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

Roll Number

12CONTENTS

o Types of Stabilityo Chemical Characteristicso Oxidationo Hydrolysis

TWO types of stability studies:1. Solid Phase stability studies2. 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.

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.

Techniques for solid state stabilities:

o Solid state NMR Spectroscopy (SSNMR)o Powder x-ray diffraction (PXRD)o Fourier transform IR (FTIR)o Raman Spectroscopyo 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 -Oxygeno -Light -Temperatureo -Ionic strength -Co solvent

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

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

FACTORS AFFECTING OXIDATION PROCESS

1) Oxygen concentration2) Light3) Heavy metals particularly those having two or more valence state4) Hydrogen & Hydroxyl Ion5) Temperature

PREVENTION OF OXIDATION

1) Reducing oxygen content2) Storage in a dark and cool condition3) Addition of chelating agent (Eg. EDTA, Citric acid, Tartaric acid)4) Adjustment of pH5) 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.).

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

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

PREVENTION OF HYDROLYSIS:

pH adjustmento Formulate the drug solution close to its pH of optimum sability.o Addition of water miscible solvent in formulationo Optimum buffer concentration

Addition of surfactanto Nonionic, cationic, and anionic surfactant stabilizes the drug against base catalysis

Salts and Esters Eg. Phosphate esters of clindamycineo The solubility of pharmaceuticals undergoing ester hydrolysis can be reduced by forming less soluble salts.o By use of complexing agent

ROLL NUMBER

19CONTENTS

o Photolysiso Racemizationo Poly/Isomerizationo Decarboxylationo Complexation

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.

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

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.

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.

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

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.

NMDA: N-Methyl D-aspartate.. A glutamate receptor

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.

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.

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

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.

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..

EXA

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REFERENCES:

o The Science & Practice of Pharmacy by Remington. (19th edition): o Physical Pharmacy by Martino Biopharmaceutics by Leon Shargelo Wikipedia-Free encyclopediao Dosage Form and Design by Ansel