PRODUCT DEVELOPMENT

ADDITIVES:

1 ADDITIVES PRESENTED BY:- NITIN KUMAR(nitinsoni57@gmail.com) RAVI KESHARI(ravikesharimpharm@gmail.com) SUNEEL PANDEY( suneel2312@rediffmail.com ) M.PHARM PSIT KANPUR 1

Definition of Pharmaceutical Additives :

2 Definition of Pharmaceutical Additives Excipients are pharmaceutical additives, the inactive ingredients used to make up a medication. They include dyes, flavors, binders, emollients, fillers, lubricants, preservatives, and many more classifications. Common excipients include cornstarch, lactose, talc, magnesium stearate, sucrose, gelatin, calcium stearate, silicon dioxide, shellac and glaze.

ANTIOXIDANTS:

3 ANTIOXIDANTS Definitions An Agent that prevents or inhibits oxidation. Antioxidants are substances that may protect cells from the damaging effects of oxygen radicals, highly reactive chemicals that play a part in atherosclerosis, some forms of cancer, and reperfusion injuries Antioxidants are used to reduce the oxidation of active substances and excipients in the finished product [1] The chemical compounds which can delay the start or slow the rate of lipid oxidation reaction. 3

Types of additives:

4 Types of additives ON BASIS OF ACTION True antioxidants- These are thought to block chain by reacting with free radicals. E.g.,butylated Hydroxytoluene. Reducing agents -These have a lower redox potential than the drug or excipient they are protecting. E.g., ascorbic acid Antioxidant synergists -These enhance the effects of antioxidants .e.g., sodium edetate [2] 4

ON BASIS OF SOURCE:

5 ON BASIS OF SOURCE Natural Antioxidants- this includes [3] vitamins herbs estrogens flavonoids amino acids beta-carotene lipid-lowering agents monounsaturated fats examples vitamin E and ascorbic acid[4] Synthetic Antioxidants- these are man made substance examples butylated hydroxytoluene, butylated hydroxyanisole and ethoxyquin.[4] 5

TYPE OF DEFENCES (MOA):

6 TYPE OF DEFENCES (MOA) Types of antioxidant defenses 1. Primary or chain breaking antioxidants (scavenger antioxidants) : These antioxidants can neutralize free radicals by donating one of their own electron, ending the electron “stealing” reaction.E.g Vitamin C , Tocopherol , Quercetin Anthocyanin 2. Secondary or preventive antioxidants : They act through numerous possible mechanisms like a) sequestration of transition metal ions which are not allowed to participate in metal catalyzed reactions. B) removal of peroxides by catalases and glutathione peroxidase , that can react with transition metal ions to produce ROS. c) removal of ROS etc. E.g. Superoxide dismutase , Catalase ,Glutathione peroxidase , Singlet oxygen quencher, Transition metal chelators (EDTA) 3. Tertiary antioxidant defenses : These are the repair processes, which remove damaged biomolecules before they can accumulate and before their presence results in altered cell metabolism and viability E.g. damaged DNA repaired by enzyme methionine sulphaoxide reductase.[3] 6

ANTIOXIDANT PROTECTION IN HUMAN BODY:

7 ANTIOXIDANT PROTECTION IN HUMAN BODY Endogenous Antioxidants • Bilirubin , • Thiols, e.g., glutathione, lipoic acid, N-acetyl cysteine ,• NADPH and NADH, • Ubiquinone (coenzyme Q10) ,• Uric acid ,• Enzymes:,– copper/zinc and manganese-dependent superoxide dismutase (SOD), – iron-dependent catalase, – selenium-dependent glutathione peroxidase. Dietary Antioxidants • Vitamin C, • Vitamin E, • Beta carotene and other carotenoids and oxycarotenoids, e.g., lycopene and lutein, • Polyphenols, e.g., flavonoids, flavones, flavonols, and Proanthocyanidins. Metal Binding Proteins • Albumin (copper) ,• Ceruloplasmin (copper), • Metallothionein (copper), • Ferritin (iron), • Myoglobin (iron), • Transferrin (iron) [5] 7

Factors Affecting the Efficiency of Antioxidant:

8 Factors Affecting the Efficiency of Antioxidant 1. Activation energy of antioxidants to donate hydrogen should be low 2. Oxidation potential should be high 3. Reduction potential should be low 4. Stability to pH and processing.

EXAMPLES OF SYNTHETIC ANTIOXIDANTS:

9 EXAMPLES OF SYNTHETIC ANTIOXIDANTS Butylated Hydroxytoluene (BHT) Chemical Name and CAS Registry Number- 2,6-Di-tert-butyl-4-methylphenol [ 128-37-0] Empirical Formula and Molecular Weight-- C 15 H 24 O 220.35 TYPICAL PROPERTIES Boiling point: 2658C Density (bulk): 0.48–0.60 g/cm3 Density (true): 1.031 g/cm3 Flash point: 1278C (open cup) Melting point: 708C Moisture content: 40.05% Partition coefficient: Octanol : water = 4.17–5.80 Refractive index: Nd 75 = 1.4859 Solubility: practically insoluble in water, glycerin, propylene glycol, solutions of alkali hydroxides, and dilute aqueous mineral acids. Freely soluble in acetone, benzene, ethanol (95%), ether, methanol, toluene, fixed oils, and mineral oil. More soluble than butylated hydroxyanisole in food oils and fats. 9

Slide 10:

10 Description Butylated hydroxytoluene occurs as a white or pale yellow crystalline solid or powder with a faint characteristic odor. Incompatibilities Butylated hydroxytoluene is phenolic and undergoes reactions characteristic of phenols. It is incompatible with strong oxidizing agents such as peroxides and permanganates. Contact with oxidizing agents may cause spontaneous combustion. Iron salts cause discoloration with loss of activity. Heating with catalytic amounts of acids causes rapid decomposition with the release of the flammable gas isobutene. Applications in Pharmaceutical Formulation or Technology Butylated hydroxytoluene is used as an antioxidant (in cosmetics, foods, and pharmaceuticals. It is mainly used to delay or prevent the oxidative rancidity of fats and oils and to prevent loss of activity of oil-soluble vitamins. Butylated hydroxytoluene is also used at 0.5–1.0% w/w concentration in natural or synthetic rubber to provide enhanced color stability. Butylated hydroxytoluene has some antiviral activity and has been used therapeutically to treat herpes simplex labialis. Stability and Storage Conditions Exposure to light, moisture, and heat causes discoloration and a loss of activity. Butylated hydroxytoluene should be stored in a well-closed container, protected from light, in a cool, dry place. 10

Butylated Hydroxyanisole (BHA):

11 Butylated Hydroxyanisole (BHA) Chemical Name and CAS Registry Number- 2-tert-Butyl-4-methoxyphenol [25013-16-5] 4 Empirical Formula and Molecular Weight- C 11 H 16 O 2 180.25 Typical Properties Antimicrobial activity: activity is similar to that of the p-hydroxy benzoate esters (parabens). The greatest activity is against molds and Gram-positive bacteria, with less activity against Gram-negative bacteria. Boiling point: 2648C at 745mmHg Density (true): 1.117 g/cm3 Flash point: 1308C Melting point: 478C (for pure 2-tert-butyl-4-methoxyphenol); Solubility: practically insoluble in water; soluble in methanol; freely soluble in 550% aqueous ethanol, propylene glycol, chloroform, ether, hexane, cottonseed oil, peanut oil, soybean oil, glyceryl monooleate, and lard, and in solutions of alkali hydroxides. Viscosity (kinematic): 3.3mm2/s (3.3 cSt) at 998C. Description Butylated hydroxyanisole occurs as a white or almost white crystalline powder or a yellowish-white waxy solid with a faint, characteristic aromatic odor. 11

Slide 12:

12 Applications in Pharmaceutical Formulation or Technology Butylated hydroxyanisole is an antioxidant with some antimicrobial properties. It is used in a wide range of cosmetics, foods, and pharmaceuticals. When used in foods, it is used to delay or prevent oxidative rancidity of fats and oils and to prevent loss of activity of oil-soluble vitamins. Butylated hydroxyanisole is frequently used in combination with other antioxidants, particularly butylated hydroxytoluene and alkyl gallates, and with sequestrants or synergists such as citric acid. FDA regulations direct that the total content of antioxidant in vegetable oils and direct food additives shall not exceed 0.02% w/w (200 ppm) of fat or oil content or essential (volatile) oil content of food. USDA regulations require that the total content of antioxidant shall not exceed 0.01% w/w (100 ppm) of any Stability and Storage Conditions Exposure to light causes discoloration and loss of activity. Butylated hydroxyanisole should be stored in a well-closed container, protected from light, in a cool, dry place. Incompatibilities Butylated hydroxyanisole is phenolic and undergoes reactions characteristic of phenols. It is incompatible with oxidizing agents and ferric salts. Trace quantities of metals and exposure to light cause discoloration and loss of activity. 12

Examples of natural antioxidants:

13 Examples of natural antioxidants Ascorbic Acid Chemical Name and CAS Registry Number- L-(þ)-Ascorbic acid [50-81-7] Empirical Formula and Molecular Weight- C 6 H 8 O 6 176.13 Typical Properties Acidity/alkalinity: pH = 2.1–2.6 (5% w/v aqueous solution) Density (bulk): 0.7–0.9 g/cm3 for crystalline material; 0.5–0.7 g/cm3 for powder. Density (particle): 1.65 g/cm3 Density (tapped): .0–1.2 g/cm3 for crystalline material; 0.9–1.1 g/cm3 for powder. Density (true): 1.688 g/cm3 Dissociation constant: pKa1 = 4.17; pKa2 = 11.57. Melting point: 1908C (with decomposition) Moisture content: 0.1% w/w Solubility: see Table Table : Solubility of ascorbic acid. 13 Table :- Solvent Solubility at 208C Chloroform Practically insoluble Ethanol 1 in 50 Ethanol (95%) 1 in 25 Ether Practically insoluble Fixed oils Practically insoluble Glycerin 1 in 1000 Propylene glycol 1 in 20 Water 1 in 3.5

Slide 14:

14 Description Ascorbic acid occurs as a white to light-yellow-colored, nonhygroscopic, odorless, crystalline powder or colorless crystals with a sharp, acidic taste. It gradually darkens in color upon exposure to light. Stability and Storage Conditions In powder form, ascorbic acid is relatively stable in air. In the absence of oxygen and other oxidizing agents it is also heat stable. Ascorbic acid is unstable in solution, especially alkaline solution, readily undergoing oxidation on exposure to the air.( The oxidation process is accelerated by light and heat and is catalyzed by traces of copper and iron. Ascorbic acid solutions exhibit maximum stability at about pH 5.4. Solutions may be sterilized by filtration. The bulk material should be stored in a well-closed nonmetallic container, protected from light, in a cool, dry place. Applications in Pharmaceutical Formulation or Technology Ascorbic acid is used as an antioxidant in aqueous pharmaceutical formulations at a concentration of 0.01–0.1% w/v. Ascorbic acid has been used to adjust the pH of solutions for injection, and as an adjunct for oral liquids. It is also widely used in foods as an antioxidant. Ascorbic acid has also proven useful as a stabilizing agent in mixed micelles containing tetrazepam.. Incompatibilities Incompatible with alkalis, heavy metal ions, especially copper and iron, oxidizing materials, methenamine, phenylephrine hydrochloride, pyrilamine maleate, salicylamide, sodium nitrite, sodium salicylate, theobromine salicylate, and picotamide.. Additionally, ascorbic acid has been found to interfere with certain colorimetric assays by reducing the intensity of the color produced. 14

SURFACTANTS:

15 SURFACTANTS surfactant (short for surface-active-agent) designates a substance which exhibits some superficial o interfacial activity. [6] Surfactants or surface active agents are broadly defined as organic compounds that can enhance cleaning efficiency, emulsifying, wetting, dispersing, solvency, foaming/ defoaming and lubricity of water-based compositions.[7] Surfactants are also known as amphiphils, colloidal electrolyte, amphipathic compounds.[8] 15

Surfactant classification :

16 Surfactant classification • According to charges: A. Ionic – Anionic – Anionic surfactants are the largest group accounting for approximately 40% of world production. These products exhibit superior wetting and emulsifying properties and tend to be higher-foaming materials [7].e.g. sodium stearate, sodium lauryl sulphate CH 3 (CH 2 ) 11 OSO 3 - Na+ – Cationic – Cationics typically have excellent antibacterial properties, provide good corrosion protection and can be good demulsifiers [7]e.g. quaternary ammonium compounds, hexadecyl trimethyl ammonium bromide (cetrimide ). B. Nonionic – Nonionic surfactants are the second largest group by volume at about 35%. Demand for these sugar-based products is escalating due to their low toxicity [7] e.g. polyethylene oxide -Sorbitan mono- oleate (Span)-Polyoxyethylene (CH 3 CH 2 O) Sorbitan monooleate (Polysorbate 80 = Tween 80) C. Amphoteric Surfactants- Amphoterics can behave as a cation or anion depending on pH. These surfactants are“mild”. E.g., Amine condensates[7] 16

• According to HLB Values: :

17 • According to HLB Values: – Anti-foaming agent (HLB=0-3) – Emulsifying agent w/o (HLB=4-6) – Wetting/spreading agent (HLB=7-9) – Emulsifying agent o/w (HLB=8-18) – Detergent (HLB=13-15) – Solubilising agent (HLB=10-18) 17

Types and Chemical Structures of Surfactants:

18 Types and Chemical Structures of Surfactants 18

Mechanism of Surfactant’s Applications:

19 Mechanism of Surfactant’s Applications • Adsorption and micellisation. • Adsorption – basic function of wetting, spreading, suspending and emulsifying , detergents , foaming , antifoaming agents • Micellisation – basic function of solubilizing agent. 19

Example of anionic surfactant:

20 Example of anionic surfactant Sodium Lauryl Sulfate Chemical Name and CAS Registry Number Sulfuric acid monododecyl ester sodium salt [151-21-3] Empirical Formula and Molecular Weight C 12 H 25 NaO 4 S 288.38 Typical Properties Acidity/alkalinity: pH = 7.0–9.5 (1% w/v aqueous solution) Acid value: 0 Antimicrobial activity: sodium lauryl sulfate has some bacteriostatic action against Gram-positive bacteria but isineffective against many Gram-negative microorganisms. It potentiates the fungicidal activity of certain substances such as sulfanilamide and sulfathiazole. Critical micelle concentration: 8.2 mmol/L (0.23 g/L) at 208C Density: 1.07 g/cm3 at 208C HLB value: 40 Interfacial tension: 11.8mN/m (11.8 dynes/cm) for a 0.05% w/v solution (unspecified nonaqueous liquid) at 308C. Melting point: 204–2078C (for pure substance) Moisture content: 45%; sodium lauryl sulfate is not hygroscopic. 20

Slide 21:

21 Solubility: freely soluble in water, giving an opalescent solution; practically insoluble in chloroform and ether. Spreading coefficient: 7.0 (0.05% w/v aqueous solution) at 308C Surface tension: 25.2mN/m (25.2 dynes/cm) for a 0.05% w/v aqueous solution at 308C Wetting time (Draize test): 118 seconds (0.05% w/v aqueous solution) at 308C. Description Sodium lauryl sulfate consists of white or cream to pale yellowcolored crystals, flakes, or powder having a smooth feel, a soapy, bitter taste, and a faint odor of fatty substances. Stability and Storage Conditions Sodium lauryl sulfate is stable under normal storage conditions. However, in solution, under extreme conditions, i.e., pH 2.5 or below, it undergoes hydrolysis to lauryl alcohol and sodium bisulfate. The bulk material should be stored in a well-closed container away from strong oxidizing agents in a cool, dry place. Incompatibilities Sodium lauryl sulfate reacts with cationic surfactants, causing loss of activity even in concentrations too low to cause precipitation. Unlike soaps, it is compatible with dilute acids and calcium and magnesium ions. Solutions of sodium lauryl sulfate (pH 9.5–10.0) are mildly corrosive to mild steel, copper, brass, bronze, and aluminum. Sodium lauryl sulfate is also incompatible with some alkaloidal salts and precipitates with lead and potassium salts. Applications in Pharmaceutical Formulation or Technology Sodium lauryl sulfate is an anionic surfactant employed in a wide range of nonparenteral pharmaceutical formulations and cosmetics; It is a detergent and wetting agent effective in both alkaline and acidic conditions. In recent years it has found application in analytical electrophoretic techniques: SDS (sodium dodecyl sulfate) polyacrylamide gel electrophoresis is one of the more widely used techniques for the analysis of proteins;(1) and sodium lauryl sulfate has been used to enhance the selectivity of micellar electrokinetic chromatography (MEKC). 21

EXAMPLE OF CATIONIC SURFACTANTS:

22 EXAMPLE OF CATIONIC SURFACTANTS Cetrimide Chemical Name and CAS Registry Number - Cetrimide [8044-71-1] Empirical Formula and Molecular Weight- C17H38BrN 336.40 Typical Properties Acidity/alkalinity: pH = 5.0–7.5 (1% w/v aqueous solution) Antimicrobial activity : cetrimide has good bactericidal activity against Gram-positive species but is less active against Gram-negative species. Pseudomonas species, particularly Pseudomonas aeruginosa , may exhibit resistance. Cetrimide is most effective at neutral or slightly alkaline pH values, with activity appreciably reduced in acidic media and in the presence of organic matter. The activity of cetrimide is enhanced in the presence of alcohols. Cetrimide has variable antifungal activity, is effective against some viruses, and is inactive against bacterial spores. Typical minimum inhibitory concentrations (MICs) Critical micelle concentration: 0.01% Melting point : 232–2478C Moisture content : at 40–50% relative humidity and 208C, cetrimide absorbs sufficient moisture to cause caking and retard flow properties. Partition coefficients: Liquid paraffin : water = <1; Vegetable oil : water = <1.

Slide 23:

23 Solubility: freely soluble in chloroform, ethanol (95%), and water; practically insoluble in ether. A 2% w/v aqueous solution foams strongly on shaking. Description Cetrimide is a white to creamy white, free-flowing powder, with a faint but characteristic odor and a bitter, soapy taste. Applications in Pharmaceutical Formulation or Technology Cetrimide is a quaternary ammonium compound that is used in cosmetics and pharmaceutical formulations as an antimicrobial preservative; It may also be used as a cationic surfactant. In eye-drops, it is used as a preservative at a concentration of 0.005% w/v. Therapeutically, cetrimide is used in relatively high concentrations, generally as 0.1–1.0% w/v aqueous solutions, as a topical antiseptic for skin, burns, and wounds. Solutions containing 1–3% w/v cetrimide are used as shampoos to remove the scales in seborrhea. Cetrimide is also used as a cleanser and disinfectant for hard contact lenses, although it should not be used on soft lenses; as an ingredient of cetrimide emulsifying wax, and in o/w creams Stability and Storage Conditions- Cetrimide is chemically stable in the dry state, and also in aqueous solution at ambient temperatures. Aqueous solutions may be sterilized by autoclaving. Water containing metal ions and organic matter may reduce the antimicrobial activity of cetrimide. The bulk material should be stored in a well-closed container in a cool, dry place. Incompatibilities Incompatible with soaps, anionic surfactants, high concentrations of nonionic surfactants, bentonite, iodine, phenylmercuric nitrate, alkali hydroxides, and acid dyes. Aqueous solution react with metals

EXAMPLE OF NONIONIC:

24 EXAMPLE OF NONIONIC Cetyl alcohol Chemical Name and CAS Registry Number- Hexadecan-1-ol [36653-82-4] Empirical Formula and Molecular Weight- C 16 H 34 O 242.44 (for pure material) Typical Properties Boiling point: 316–3448C;3448C for pure material. Density: 0.908 g/cm3 Flash point: 1658C Melting point: 45–528C;498C for pure material. Refractive index: nD79 = 1.4283 for pure material. Solubility: freely soluble in ethanol (95%) and ether, solubility increasing with increasing temperature; practically insolublein water. Miscible when melted with fats, liquid and solid paraffins, and isopropyl myristate. Specific gravity: 0.81 g/cm3 at 508C Viscosity (dynamic): 7 mPa s (7 cP) at 508C Description Cetyl alcohol occurs as waxy, white flakes, granules, cubes, or castings. It has a faint characteristic odor and bland taste.

Slide 25:

25 Stability and Storage Conditions Cetyl alcohol is stable in the presence of acids, alkalis, light, and air; it does not become rancid. It should be stored in a well closed container in a cool, dry place. Incompatibilities Incompatible with strong oxidizing agents. Cetyl alcohol is responsible for lowering the melting point of ibuprofen, which results in sticking tendencies during the process of film coating ibuprofen crystals. Applications in Pharmaceutical Formulation or Technology Cetyl alcohol is widely used in cosmetics and pharmaceutical formulations such as suppositories, modified-release solid dosage forms, emulsions, lotions, creams, and ointments. In suppositories cetyl alcohol is used to raise the melting point of the base, and in modified-release dosage forms it may be used to form a permeable barrier coating. In lotions, creams, and ointments cetyl alcohol is used because of its emollient, water-absorptive, and emulsifying properties. It enhances stability, improves texture, and increases consistency. The emollient properties are due to absorption and retention of cetyl alcohol in the epidermis, where it lubricates and softens the skin while imparting a characteristic ‘velvety’ texture.

EXAMPLE OF AMPHOTERIC SURFACTANTS:

26 EXAMPLE OF AMPHOTERIC SURFACTANTS L-Proline Chemical name and CAS no.- Pyrrolidine-2-carboxylic acid 147-85-3 Empirical formula and Molecular wt -C 5 H 9 NO 2 115.13 Typical Properties Isoelectric point (pH) -6.30 pKa values -1.99, 10.60 Melting Point -230 C (Decomposes) Partition Coefficient : 2.68 Vapor Pressure: 0.001 25C Boiling Point :299 C Heat Of Vaporization- 53.9 kJ/mol Heat Of Combustion- 6388 kJ/mol Specific rotation = +84.5° ~ +85.5° Solubilty - soluble in water, readily soluble in alcohol

Slide 27:

27 Storage Keep in a cool, dry, dark location in a tightly sealed container or cylinder. Keep away from incompatible materials, ignition sources and untrained individuals. Secure and label area. Protect containers/cylinders from physical damage. Stability -Impure L-Proline is hygroscopic Incompatibilities Incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides Flammable gaseous hydrogen is generated in combination with strong reducing agents, such as hydrides . Applications in Pharmaceutical Formulation or Technology L-ProlineBentaines is an osmoprotectant and therefore is used in many pharmaceutical, biotechnological applications. In brewing, proteins rich in proline combine with polyphenols to produce haze (turbidity).

GLIDANTS:

28 GLIDANTS A glidant is a substance that is added to a powde r to improve its . These materials are always added in the dry state just prior to compression. MODE ACTION OF GLIDANTS A Glidant's effect is due to a counter-action to factors resulting in poor flowability of powders. For instance, correcting surface irregularity, reducing interparticular friction & decreasing surface charge. The result is a decrease in the angle of repose which is an indication of an enhanced powder's flowability.

EXAMPLE OF GLIDANTS:

29 EXAMPLE OF GLIDANTS Talc Chemical Name and CAS Registry Number- Talc [14807-96-6] Empirical Formula and Molecular Weight- Talc is a purified, hydrated, magnesium silicate, approximating to the formula Mg6(Si2O5)4(OH)4. It may contain small,variable amounts of aluminum silicate and iron. Typical Properties Acidity/alkalinity: pH = 7–10 for a 20% w/v aqueous dispersion. Hardness (Mohs): 1.0–1.5 Moisture content : talc absorbs insignificant amounts of water at 258C and relative humilities up to about 90%. Particle size distribution: varies with the source and grade of material. Two typical grades are 599% through a 74 mm (#200 mesh) or 599% through a 44 mm (#325 mesh). Refractive index: nD 20 = 1.54–1.59 Solubility: practically insoluble in dilute acids and alkalis,organic solvents, and water. Specific gravity: 2.7–2.8 Specific surface area: 2.41–2.42m2/g Description Talc is a very fine, white to grayish-white, odorless, impalpable, unctuous, crystalline powder. It adheres readily to the skin and is soft to the touch and free from grittiness

Slide 30:

30 Stability and Storage Conditions Talc is a stable material and may be sterilized by heating at 1608C for not less than 1 hour. It may also be sterilized by exposure to ethylene oxide or gamma irradiation. Talc should be stored in a well-closed container in a cool, dry place. Incompatibilities Incompatible with quaternary ammonium compounds Applications in Pharmaceutical Formulation or Technology Talc was once widely used in oral solid dosage formulations as a lubricant and diluents, although today it is less commonly used. However, it is widely used as a dissolution retardant in the development of controlled-release products. Talc is also used as a lubricant in tablet formulations; in a novel powder coating for extended-release pellets; and as an adsorbant. In topical preparations, talc is used as a dusting powder, although it should not be used to dust surgical gloves; Talc is a natural material; it may therefore frequently contain microorganisms and should be sterilized when used as a dusting powder. Talc is additionally used to clarify liquids and is also used in cosmetics and food products, mainly for its lubricant properties

STARCH:

31 STARCH Chemical Name and CAS Registry Number- Starch [9005-25-8] Empirical Formula and Molecular Weight- (C6H10O5)n 50 000–160 000 where n = 300–1000. Starch consists of amylose and amylopectin, two polysaccharides based on a-glucose. Typical Properties Acidity/alkalinity: pH = 5.5–6.5 for a 2% w/v aqueous dispersion of corn starch, at 258C. Density (bulk): 0.462 g/cm3 for corn starch. Density (tapped): 0.658 g/cm3 for corn starch. Density (true): 1.478 g/cm3 for corn starch. Flowability : 10.8–11.7 g/s for corn starch;(9) 30% for corn starch (Carr compressibility index). Corn starch is cohesive and has poor flow characteristics. Gelatinization temperature : 738C for corn starch; 728C for potato starch; 638C for wheat starch. Moisture content: all starches are hygroscopic and rapidly absorb atmospheric moisture.(21,22) Approximate equilibrium moisture content values at 50% relative humidity are 11% for corn starch; 18% for potato starch; 14% for rice starch; and 13% for wheat starch. Between 30% and 80% relative humidity, corn starch is the least hygroscopic starch and potato starch is the most hygroscopic. Commercially available grades of corn starch usually contain 10–14% water. Particle size distribution: Corn starch: 2–32 mm; Potato starch: 10–100 mm; Rice starch: 2–20 mm; Tapioca starch: 5–35 mm; Wheat starch: 2–45 mm. Median diameter for corn starch is 17 mm and for wheat starch is 23 mm.

Slide 32:

32 Solubility: practically insoluble in cold ethanol (95%) and in cold water. Starch swells instantaneously in water by about 5–10% at 378C.(2,22) Polyvalent cations produce more swelling than monovalent ions, but pH has little effect. Specific surface area: 0.41–0.43m2/g for corn starch; 0.12m2/g for potato starch; 0.27–0.31m2/g for wheat starch. Swelling temperature: 658C for corn starch; 648C for potato starch; 558C for wheat starch. Viscosity (dynamic): 13.0 mPa s (13.0 cP) for a 2%w/v aqueous dispersion of corn starch at 258C. Stability and Storage Conditions Dry, unheated starch is stable if protected from high humidity. When used as a diluents or disintegrant in solid-dosage forms,starch is considered to be inert under normal storage conditions. However, heated starch solutions or pastes are physically unstable and are readily attacked by microorganisms to form a wide variety of starch derivatives and modified starches that have unique physical properties. Starch should be stored in an airtight container in a cool, dry place. Applications in Pharmaceutical Formulation or Technology Starch is used as an excipient primarily in oral solid-dosage formulations where it is utilized as a binder, diluent, and disintegrant.As a diluent, starch is used for the preparation of standardized triturates of colorants or potent drugs to facilitate subsequent mixing or blending processes in manufacturing operations. Starch is also used in dry-filled capsule formulations for volume adjustment of the fill matrix. In tablet formulations, freshly prepared starch paste is used at a concentration of 5–25% w/w in tablet granulations as a binder. Selection of the quantity required in a given system is determined by optimization studies, using parameters such as granule friability, tablet friability, hardness, disintegration rate, and drug dissolution rate. Starch is one of the most commonly used tablet disintegrants at concentrations of 3–15% w/w.(2–9) However, unmodified starch does not compress well and tends to increase tablet friability and capping if used in high concentrations. In granulated formulations, about half the total starch content is included in the granulation mixture and the balance as part of the final blend with the dried granulation. Also, when used as adisintegrant, starch exhibits type II isotherms and has a high specific surface for water sorption.

Slide 33:

33 Starch has been investigated as an excipient in novel drug delivery systems for nasal, oralperiodontal,and other site-specific delivery systems. Starch is also used in topical preparations; for example, it is widely used in dusting powders for its absorbency, and is used as a protective covering in ointment formulations applied to the skin. Starch mucilage has also been applied to the skin as an emollient, has formed the base of some enemas, and has been used in the treatment of iodine poisoning. Therapeutically, rice starch-based solutions have been used in the prevention and treatment of dehydration due to acute diarrheal diseases.

MAGNESIUM STEARATE:

34 MAGNESIUM STEARATE Chemical Name and CAS Registry Number- Octadecanoic acid magnesium salt [557-04-0] Empirical Formula and Molecular Weight- C36H70MgO4 591.34 Typical Properties Crystalline forms: high-purity magnesium stearate has been isolated as a trihydrate, a dihydrate, and an anhydrate. Density (bulk): 0.159 g/cm3 Density (tapped): 0.286 g/cm3 Density (true): 1.092 g/cm3 Flash point: 2508C Flowability: poorly flowing, cohesive powder. Melting range: 117–1508C (commercial samples); 126–1308C (high purity magnesium stearate). Solubility: practically insoluble in ethanol, ethanol (95%), ether and water; slightly soluble in warm benzene and warm ethanol (95%). Specific surface area: 1.6–14.8m2/g

Slide 35:

35 Description Magnesium stearate is a very fine, light white, precipitated or milled, impalpable powder of low bulk density, having a faint odor of stearic acid and a characteristic taste. The powder is greasy to the touch and readily adheres to the skin. Applications in Pharmaceutical Formulation or Technology Magnesium stearate is widely used in cosmetics, foods, and pharmaceutical formulations. It is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5.0% w/w. It is also used in barrier creams. Stability and Storage Conditions Magnesium stearate is stable and should be stored in a well closed container in a cool, dry place. Incompatibilities Incompatible with strong acids, alkalis, and iron salts. Avoid mixing with strong oxidizing materials. Magnesium stearate cannot be used in products containing aspirin, some vitamins, and most alkaloidal salts.

Methods to determine incompatibilty :

36 Methods to determine incompatibilty - DSC ( Differential Scanning Calorimetry ) - FTIR (Fourier Transform Infrared) - HPLC (High Performance Liquid Chromatography) - LIQUID CHROMATOGRAPHY 36

DSC:

37 DSC The sample and reference are maintained at the same temperature, even during a thermal event (in the sample) The energy required to maintain zero temperature differential between the sample and the reference, d D q / d t , is measured 37

Slide 38:

38 Basic Principles of Thermal Analysis Modern instrumentation used for thermal analysis usually consists of four parts: sample/sample holder sensors to detect/measure a property of the sample and the temperature an enclosure within which the experimental parameters may be controlled a computer to control data collection and processing power compensated DSC heat flux DSC

Slide 39:

39 DSC differs fundamentally from DTA in that the sample and reference are both maintained at the temperature predetermined by the program. during a thermal event in the sample, t he system will transfer heat to or from the sample pan to maintain the same temperature in reference and sample pans two basic types of DSC instruments: power compensation and heat-flux Differential Scanning Calorimetry power compensation DSC heat flux DSC

Slide 40:

40 DSC Calibration baseline evaluation of the thermal resistance of the sample and reference sensors measurements over the temperature range of interest 2-step process the temperature difference of two empty crucibles is measured the thermal response is then acquired for a standard material, usually sapphire, on both the sample and reference platforms amplified DSC signal is automatically varied with temperature to maintain a constant calorimetric sensitivity with temperature

Slide 41:

41 Typical Features of a DSC Trace for a Polymorphic System sulphapyridine endothermic events melting sublimation solid-solid transitions desolvation chemical reactions exothermic events crystallization solid-solid transitions decomposition chemical reactions baseline shifts glass transition

Slide 42:

42 Melting Processes by DSC pure substances linear melting curve melting point defined by onset temperature impure substances concave melting curve melting characterized at peak maxima eutectic impurities may produce a second peak melting with decomposition exothermic endothermic eutectic melt

THANKS:

43 THANKS 43

Slide 44:

44

Slide 45:

45

Slide 46:

46 1.Antioxidants and Cardiovascular Health Vishal R. Tandon*, S. Verma, J. B. Singh, Annil Mahajan From The Postgraduate Department of *Pharmacology & Therapeutics and General Medicine, Govt. Medical College, Jammu. DRUGREVIEW Correspondece to: Dr. Vishal R Tandon, Sr. Demonstrator, P.G Department of Pharmacology & Therapeutics, Govt. Medical College, Jammu. 2.INCLUSION OF ANTIOXIDANTS AND ANTIMICROBIAL PRESERVATIVES IN MEDICINAL PRODUCTS. Last revised July 1997 3.Antioxidants and Coronary Artery Disease. Jason M. Lazar, MDGeorgeYiachos, MD Winthrop-University Hospital 4.Antioxidants:function, types and necessity of inclusion in pet foods John W. Hilton, Ph.D. Nutrition alimentation. 46 5.Antioxidants BY DR. MARK PERCIVAL. NUT031 1/96 Rev. 10/98 CLINICAL NUTRITION INSIGHTS Copyright © 1996 Advanced Nutrition Publications, Inc., Revised 1998

Slide 47:

47 47 6.LABORATORY OF FORMULATION, INTERFACES RHEOLOGY AND PROCESSES UNIVERSIDAD DE LOS ANDES FACULTAD DE INGENIERIA ESCUELA DE INGENIERIA QUIMICA SURFACTANTS Types and Uses Jean-Louis SALAGER 7.SURFACTANTS A Market Opportunity Study Update Prepared for the United Soybean Board December 2008

Reaction of antioxidants with radicals:

48 Reaction of antioxidants with radicals R · + AH RH + A RO + AH ROH + A ROO + AH ROOH + A R + A RA RO + A ROA ROO + A ROOA Antioxidant + O 2 Oxidized Antioxidant · · · · · · · · · · ·