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11. Annexures
11. ANNEXURES Annexure I
Drug Profiles
I-A. MEBENDAZOLE(1-7)
Generic Name: Mebendazole
Chemical IUPAC Name: Methyl 5-benzoyl-2-benzimidazolecarbamate
Empirical Formula:C16H13N3O3
Molecular weight: 295.3 g/mol
Structural Formula:
Appearance: White to slightly yellow amorphous powder almost colorless
Solubility: Insoluble in water and most of the organic solvents; freely soluble in formic
acid, dimethylsulphoxide Melting point: 288.5OC
Log P/Hydrophicity: 2.8
Mechanism of action: Although the exact mechanism of anthelmintic activity of
mebendazole has not been fully elucidated, the drug appears to cause selective and
irreversible inhibition of the uptake of glucose and other low molecular weight nutrients
in susceptible helminths; inhibition of glucose uptake appears to result in endogenous
depletion of glycogen stores in the helminth. Mebendazole does not inhibit glucose
uptake in mammals. Mebendazole appears to cause degenerative changes in the intestine
of nematodes and in the absorptive cells of cestodes. The principal anthelmintic effect of
the drug appears to be degeneration of cytoplasmic microtubules within these intestinal
and absorptive cells. Microtubular deterioration results in inhibition of organelle
movement and interferes with the absorptive and secretory function. As a result of
excessive accumulation of intracellular transport secretory granules, hydrolytic and
proteolytic enzymes are released and cause cellular autolysis. This irreversible damage
leads to death of the parasite.
Pharmacokinetics:
Absorption: Mebendazole appears to be minimally absorbed from the GI tract following
oral administration. Limited data indicate that about 2–10% of an oral dose is absorbed.
Peak plasma concentrations of mebendazole occur approximately 0.5–7 hours after oral
administration of the drug and exhibit wide interpatient variation. Following oral
administration of multiple doses of mebendazole (40 mg/kg daily) to 2 adults with
hydatid cysts, mean peak plasma concentrations of about 0.08 mcg/mL occurred at 0.5–2
hours. Following oral administration of a single 10-mg/kg dose of mebendazole to
patients with hydatid cysts in another study, peak plasma concentrations of about 0.02–
0.5 mcg/mL occurred at 1.5–7.25 hours. Following oral administration of multiple doses
of mebendazole (100 mg 2 times daily for 3 days) to several children, peak plasma
mebendazole concentrations did not exceed 0.03 mcg/mL and peak plasma
concentrations of the 2-amino metabolite of the drug (the major metabolite) did not
exceed 0.09 mcg/ml.
Distribution: Mebendazole is highly bound to plasma proteins.
Metabolism: Although the exact metabolic fate of mebendazole has not been fully
determined, the drug is metabolized via decarboxylation to 2-amino-5(6)-benzimidazolyl
phenylketone; this metabolite does not have anthelmintic activity.
Elimination: The elimination half-life of mebendazole has been reported to be about
2.8–9 hours. Approximately 2–10% of an oral dose of mebendazole is excreted in urine
within 24–48 hours of administration, principally as unchanged drug and the 2-amino
metabolite. The metabolic fate and rate of excretion of unabsorbed mebendazole have not
been determined.
Category: Anthelmintic
Indications: For the treatment of a variety of nematode (roundworm) infections,
including trichuriasis (whipworm infection), enterobiasis (pinworm infection), ascariasis
(roundworm infection), hookworm infections and hydatid disease
The drug’s broad spectrum of activity makes it useful in the treatment of mixed
helminthic infections.
Dose: The dose vary depending upon the type of infection and age of the patient.
Toxicity: Overdosage of mebendazole may result in GI symptoms lasting up to a few
hours. If acute overdosage of mebendazole occurs, vomiting and purging should be
induced.
Adverse effects: Mebendazole is well tolerated even by patients in poor health.
Diarrhoea, nausea and abdominal pain have attended its use in heavy infestation. Allergic
reactions, loss of hair and granulocytopenia have been reported with high doses. Safety of
Mebendazole during pregnancy is not known, but it is contraindicated on the basis of
animal data.
Drug Interactions: Reduced plasma levels with enzyme inducres e.g. phenytoin,
carbamazepine. Increased plasma levels with cimetidine
Dosage Forms: Tablets (100 mg), Suspension (100mg/5ml)
Table-11.1 Marketed Formulations of Mebendazole
Sr. No. Product Name Dosage form Name of company
1 Helmintol Tablet, Suspension Medley
2 Lupimeb Tablet Lupin
3 Mebazole Tablet Ranbaxy
4 Mebex Tablet, Suspension Cipla
5 Wormin Tablet, Suspension Cadila
6 Mendazole Tablet Glaxo Smith Kline
I-B LOVASTATIN [1-4,8,9]
Generic Name: Lovastatin
Chemical IUPAC Name: 1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-
oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl
(2S)-2-methylbutanoate
Empirical Formula: C24H36O5
Molecular weight: 404.55 g/mol
Structural Formula:
Appearance: White, nonhygroscopic crystalline powder
Solubility: Insoluble in water and sparingly soluble in ethanol, methanol, and
acetonitrile Melting point: 174.5OC
Log P/Hydrophicity: 4.5
Mechanism of action: Lovastatin is a lactone that is readily hydrolyzed in vivo to
the corresponding b-hydroxyacid, a potent inhibitor of HMG-CoA reductase, the enzyme
that catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA
to mevalonate is an early step in the biosynthetic pathway for cholesterol.
Pharmacokinetics:
Absorption: It is incompletely absorbed for g.i.t. and its oral bioavailabiity is 30%.
Distribution: It is highly bound to proteins
Metabolism: Lovastatin undergoes extensive first-pass extraction in the liver.
Elimination: Metabolites are mainly excreted in bile and elimination half-life is 5.3
hours.
Category: Hypolipidaemic drug
Indications: The first choice drugs for primary hyperlipidaemias with raised LDL and
total CH levels, with or without raised TG levels, as well as for secondary
hypercholesterolaemia. For primary propylaxis of coronary artery disease
Dose: 10-40 mg/day (max. 80 mg)
Toxicity:
Adverse effects: Increased creatine phosphokinase; flatulence, nausea, dyspepsia,
constipation or diarrhoea, abdominal pain;muscle cramps, myalgia, weakness; blurred
vision; headache, dizziness; rash.
Drug Interactions: Reduced absorption with cholestryamine, isradipine. It may increase
warfarin effect. Increase risk of myopahty & rhabdomyolysis with amiodarone, fibrates,
danazol, niacin, verapamil, protease inhibitors. Increased levels with diclofenac,
doxycycline, isoniazid, quinidine, diltiazem.
Dosage Forms: Tablets (10mg, 20mg)
Table-11.2 Marketed Formulations of Lovastatin
Sr. No. Product Name Dosage form Name of company
1 Aztatin Tablet Sun
2 Elstatin Tablet Glenmark
3 Lestric Tablet Ranbaxy
4 Lotin Tablet Intas
References:
1. Goodman and Gilman’s Pharmacological Basis of Therapuetics/ Ed by Joel G.
Hardman and Lee E. Limbird, 10th edition, Mc-Graw Hill, Inc., New York, 2001.
2. Essentials of Medical Pharmacology Ed by K. D. Tripathi, 6th edition, Jaypee,
India, 2008, 807-809.
3. Rang and Dale’s Pharmacology Churchill Livingstone/Ed by Rang H P.; Dale
M.M.; Ritter J.M.; Flower R.J., 6th ed.,2007,714.
4. The Merck Index 11th ed., Merck Research Laboratories,1989,904.
5. Van den Bossche H. Rochette F. Horig C.,1982. Mebendazole and related
anthelmintics. Adv.Pharmaco Chemother.19,287-296
6. Kumar A.,Chattopadhyay T.K.,1992. Management of hydatid disease
of the liver. Postgrad.Med.J.68:853-856.
7. Erdincler P.; Kaynar M. Y.; Babuna O.; Canbaz B.,1997. The role of
mebendazole in surgical treatment of central nervous system hydatid disease. Br.
J. Neurosurg. 11(2):116-120.
8. W. Jacobsen et. al (1999) Small Intestinal Metabolism of the 3-Hydroxy-3-
methylglutaryl-Coenzyme A Reductase Inhibitor Lovastatin and Comparison with
Pravastatin . The Journal of Pharmacology and experimental therapeutics 29(1):
131-139.
9. Henwood JM and Heel RC (1988) Lovastatin: A preliminary review of its
Pharmacodynamic properties and therapeutic use in hyperlipidemia. Drugs
36:429–454.
Annexure II
Identification and Estimation of Drugs
II-A. MEBENDAZOLE
IDENTIFICATION:
1. Melting Point Determination: Melting point is the temperature at which the pure liquid and solid exist in equilibrium.
The Thiel’s tube method of melting point determination in liquid paraffin was used in the
present study. The melting point of Mebendazole was found to be 289oC. This matches
with the standard melting point (288.5oC) indicating the identity of the drug. [1]
2. UV Spectrum: UV scanning was done for pure drug from 200-400nm in 0.1M HCl by Shimazdu UV-
1601, Japan. The λmax was found at 245 nm.
3. FTIR Spectra: FTIR spectra of drug in KBr pellets at moderate scanning speed between 4000-600 cm-1
was made. The spectrum is shown in figure 11.1. The peak related to the functional group
present in standard drug and procured drug are given in Table 10.3.
Figure 11.1 FTIR Spectra of Procured Mebendazole
Table 11.3 Results of FTIR Study of Mebendazole
Functional Group present Standard drug Procured drug[2]
NH stretching 3415 3420
C=O (amide) 1720 1720
C=O 1650 1650
CH3-O 1410-1460 1410-1460
The procured drug shows similarity with the reported value of functional group present in
standard drug, which indicates purity and identity of Mebendazole.
4. Selection of dissolution Medium: Mebendazole is insoluble in water. Thus, proper selection of dissolution medium for
Mebendazole was found essential as these drugs attain saturation solubility quickly in the
dissolution medium which may affect the release behavior of the drug loading to the poor
release behavior. MBZ has three polymorphic forms (A, B and C) that have different
solubility and therapeutic effects.5 In 0.1 M HCl polymorph C dissolves faster when
compared to polymorph B and polymorph A.5 Polymorphic form C is pharmaceutically
favoured.5
5. Estimation of drug: UV spectroscopic method was selected for the estimation of the drug.
6. Preparation of dissolution Medium: 8.5 ml of concentrated hydrocholoric acid was taken in 1000 ml volumetric flask and
diluted with distilled deionized water upto the mark. The pH was adjusted to 1.2.
7. Preparation of Standard Curve: Mebendazole (100mg) was accurately weighed and transferred into a 100 ml volumetric
flask. Volume was made up to the mark by using 0.1M HCl. This standard stock solution
is having concentration of 1000mcg/ml. From the standard stock solution, a series of
dilution were made to get 10 to 50mcg/ml solution using dissolution medium. The
absorbance of these solutions was measured at 245 nm against 0.1M HCl as a blank using
UV/VIS double beam spectrophotometer. The experiment was performed in triplicate and
based on average absorbance; the equation for the best line fit was generated. The results
of standard curve preparation are shown in Table 10.4 and Figure 11.2.
Table 11.4 Standard Curve of Mebendazole in 0.1 M HCl
Concentration
(mcg/ml)
Absorbance
1
Absorbance
1
Absorbance
1
Average
Absorbance
0 0 0 0 0
10 0.159 0.155 0.157 0.157
20 0.321 0.325 0.317 0.321
30 0.480 0.476 0.472 0.476
40 0.637 0.640 0.634 0.637
50 0.790 0.794 0.792 0.792
SUMMARY OUTPUT
Regression statistics Standard Error 0.002683
Multiple R 0.9999 Slope 0.01586
R square 0.9999 Intercept 0.0008
Adjusted R
square
0.9998
Observations 6
Absorbance = Slope * Concentration + Intercept
Absorbance = 0.01586 * Concentration + 0.0008
Standard curve of Mebendazole in 0.1 M HCl
0
0.2
0.4
0.6
0.8
1
0 10 20 30 40 50
Concentration (mcg/ml)
Abs
orba
nce
Figure 11.2: Standard Curve of Mebendazole in 0.1 M HCl
II-B. LOVASTATIN
IDENTIFICATION:
1. Melting Point Determination: Melting point is the temperature at which the pure liquid and solid exist in equilibrium.
The Thiel’s tube method of melting point determination in liquid paraffin was used in the
present study. The melting point of Lovastatin was found to be 175oC. This matches with
the standard melting point (174.5oC) indicating the identity of the drug. [1]
2. UV Spectrum: UV scanning was done for pure drug from 200-400nm in 0.05M Phosphate buffer pH-7
ctg. 0.25% SLS by Shimazdu UV-1601, Japan. The λmax was found at 239 nm.
3. FTIR Spectra: FTIR spectra of drug in KBr pellets at moderate scanning speed between 4000-600 cm-1
was made. The spectrum is shown in figure 11.3. The peak related to the functional group
present in standard drug and procured drug are given in Table 10.5.
Figure 11.3 FTIR Spectra of Procured Lovastatin
Table 11.5 Results of FTIR Study of Lovastatin
Functional Group present Standard drug Procured drug[3]
Lactone and ester carbonyl 1725 1730.88
Methyl asymmetric bond 1460 1457.33
Lactone C-O-C asymmetric 1260 1263.16
bend
Ester C-O-C asymmetric
stretch
1222 1227.87
The procured drug shows similarity with the reported value of functional group present in
standard drug, which indicates purity and identity of Lovastatin.
4. Selection of dissolution Medium: Water solubility of LVS is 0.0004 mg/ml. 0.05M Phosphate buffer pH-7 ctg. 0.25% SLS
was selected as a dissolution medium.6
5. Estimation of drug: UV spectroscopic method was selected for the estimation of the drug.
6. Preparation of dissolution Medium: 756 ml of 0.1 M disodium hydrogen phosphate and 244 ml of 0.1 M HCl was mixed
together to make the volume 1000 ml. The pH of above solution was adjusted to 7. In the
above solution, 2.5 gm of Sodium Lauryl Sulphate was added and dissolved.
7. Preparation of Standard Curve: Lovastatin (10mg) was accurately weighed and transferred into a 250 ml volumetric
flask. Volume was made up to the mark by using 0.05M Phosphate buffer pH-7 ctg.
0.25% SLS. This standard stock solution is having a concentration of 40mcg/ml. From
the standard stock solution, a series of dilution were made to get 20 to 40mcg/ml solution
using dissolution medium. The absorbance of these solutions was measured at 239 nm
against 0.05M Phosphate buffer pH-7 ctg. 0.25% SLS as a blank using UV/VIS double
beam spectrophotometer. The experiment was performed in triplicate and based on
average absorbance; the equation for the best line fit was generated. The results of
standard curve preparation are shown in Table 10.6 and Figure 6.
Table 11.6 Standard Curve of Lovastatin in 0.05M Phosphate buffer pH-7 ctg. 0.25%
SLS
Concentration
(mcg/ml)
Absorbance
1
Absorbance
1
Absorbance
1
Average
Absorbance
0 0 0 0 0
20 0.3038 0.3048 0.3044 0.3043
25 0.349 0.351 0.3503 0.3501
30 0.4198 0.4195 0.4201 0.4198
35 0.5133 0.5177 0.5187 0.5166
40 0.6024 0.6038 0.601 0.6024
SUMMARY OUTPUT
Regression statistics Standard Error 0.01612
Multiple R 0.9976 Slope 0.0148
R square 0.9953 Intercept 0.0062
Adjusted R
square
0.9941
Observations 6
Absorbance = Slope * Concentration + Intercept
Absorbance = 0.0148 * Concentration -0.0062
Standard Curve of Lovastatin in 0.05M Phosphate buffer pH-7 ctg. 0.25% SLS
0.30.350.4
0.450.5
0.550.6
0.65
20 25 30 35 40
Concentration (mcg/ml)
Abs
orba
nce
Figure 11.4 Standard Curve of Lovastatin in 0.05M Phosphate buffer pH-7 ctg. 0.25%
SLS
REFERENCES:
1. The Merck Index By M.J.O’Neil, Merck & Co., USA, 2001
2. Analytical Profile of Drug substance and excipients Hary G Brittain volume 16,
291
3. Analytical Profile of Drug substance and excipients. Hary G Brittain volume 21,
277
4. Indian Pharmacopoeia By Government of India, New Delhi,1996,2007
5. Swanepoel E; Liebenberg W; Devarakonda B; de villiers M M Developing a
discriminating dissolution test for three mebendazole polymorphs based on
solubility differences Die Pharmazie 2003;58(2):117-121
6. Dissolution methods database, available at
www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions
.cfm?PrintAll=1 - 300k Accessed on 20th March, 2011
Annexure III
Excipient Profiles III-A. POLY VINYL ALCOHOL [1]
1 Nonproprietary Names PhEur: Poly(Vinyl Alcohol)
USP: Polyvinyl Alcohol
2 Synonyms
Airvol; Alcotex; Celvol; Elvanol; Gelvatol; Gohsenol; Lemol; Mowiol; poly(alcohol
vinylicus); Polyvinol; PVA; vinyl alcohol polymer.
Chemical Name and CAS Registry Number
Ethenol, homopolymer [9002-89-5]
Empirical Formula and Molecular Weight
(C2H4O)n 20 000–200 000
Polyvinyl alcohol is a water-soluble synthetic polymer represented by the formula
(C2H4O)n. The value of n for commercially available materials lies between 500 and
5000, equivalent to a molecular weight range of approximately 20 000–200 000; see
Table I.
Table I: Commercially available grades of polyvinyl alcohol
5 Structural Formula
6 Functional Category
Coating agent; lubricant; stabilizing agent; viscosity-increasing agent.
7 Applications in Pharmaceutical Formulation or Technology
Polyvinyl alcohol is used primarily in topical pharmaceutical and ophthalmic
formulations; see Table II. It is used as a stabilizing agent for emulsions (0.25–3.0%
w/v). Polyvinyl alcohol is also used as a viscosity-increasing agent for viscous
formulations such as ophthalmic products. It is used in artificial tears and contact lens
solutions for lubrication purposes, in sustained-release formulations for oral
administration,(4) and in transdermal patches. Polyvinyl alcohol may be made into
microspheres when mixed with a glutaraldehyde solution.
8 Description
Polyvinyl alcohol occurs as an odorless, white to cream-colored granular powder.
9 Pharmacopeial Specifications
10 Typical Properties
Melting point
2280C for fully hydrolyzed grades;
180–190oC for partially hydrolyzed grades.
Refractive index nD
25 = 1.49–1.53
Solubility
Soluble in water; slightly soluble in ethanol (95%); insoluble in organic
solvents. Dissolution requires dispersion (wetting) of the solid in water at
room temperature followed by heating the mixture to about 908oC for
approximately 5 minutes. Mixing should be continued while the heated
solution is cooled to room temperature.
Specific gravity
1.19–1.31 for solid at 258C;
1.02 for 10% w/v aqueous solution at 258C.
Specific heat 1.67 J/g (0.4 cal/g)
Viscosity (dynamic) see Table IV.
11 Stability and Storage Conditions
Polyvinyl alcohol is stable when stored in a tightly sealed container in a cool, dry place.
Aqueous solutions are stable in corrosionresistant sealed containers. Preservatives may be
added to the solution if extended storage is required. Polyvinyl alcohol undergoes slow
degradation at 1008C and rapid degradation at 2008C; it is stable on exposure to light.
12 Incompatibilities
Polyvinyl alcohol undergoes reactions typical of a compound with secondary hydroxy
groups, such as esterification. It decomposes in strong acids, and softens or dissolves in
weak acids and alkalis. It is incompatible at high concentration with inorganic salts,
especially sulfates and phosphates; precipitation of polyvinyl alcohol 5% w/v can be
caused by phosphates. Gelling of polyvinyl alcohol solution may occur if borax is
present.
13 Safety
Polyvinyl alcohol is generally considered a nontoxic material. It is nonirritant to the skin
and eyes at concentrations up to 10%; concentrations up to 7% are used in cosmetics.
Studies in rats have shown that polyvinyl alcohol 5% w/v aqueous solution injected
subcutaneously can cause anemia and infiltrate various organs and tissues.
LD50 (mouse, oral): 14.7 g/kg
LD50 (rat, oral): >20 g/kg
14 Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity of material
handled. Eye protection and gloves are recommended. Polyvinyl alcohol dust may be an
irritant on inhalation. Handle in a well-ventilated environment.
15 Regulatory Status
Included in the FDA Inactive Ingredients Database (ophthalmic preparations and oral
tablets). Included in nonparenteral medicines licensed in the UK. Included in the
Canadian List of Acceptable Non-medicinal Ingredients.
16 Comments
Various grades of polyvinyl alcohol are commercially available. The degree of
polymerization and the degree of hydrolysis are the two determinants of their physical
properties. Pharmaceutical grades are partially hydrolyzed materials and are named
according to a coding system. The first number following a trade name refers to the
degree of hydrolysis and the second set of numbers indicates the approximate viscosity
(dynamic), in mPa s, of a 4% w/v aqueous solution at 200C.
III-B. GLYCERIN [1]
1 Nonproprietary Names BP: Glycerol
JP: Concentrated Glycerin
PhEur: Glycerol
USP: Glycerin
2 Synonyms
Croderol; E422; glicerol; glycerine; glycerolum; Glycon G-100; Kemstrene; Optim;
Pricerine; 1,2,3-propanetriol; trihydroxypropane glycerol.
3 Chemical Name and CAS Registry Number
Propane-1,2,3-triol [56-81-5]
4 Empirical Formula and Molecular Weight
C3H8O3 92.09
5 Structural Formula
6 Functional Category
Antimicrobial preservative; cosolvent; emollient; humectant; plasticizer; solvent;
sweetening agent; tonicity agent.
7 Applications in Pharmaceutical Formulation or Technology
Glycerin is used in a wide variety of pharmaceutical formulations including oral, otic,
ophthalmic, topical, and parenteral preparations; see Table I.
In topical pharmaceutical formulations and cosmetics, glycerin is used primarily for its
humectant and emollient properties. Glycerin is used as a solvent or cosolvent in creams
and emulsions. Glycerin is additionally used in aqueous and nonaqueous gels and also as
an additive in patch applications. In parenteral solvent. formulations, glycerin is used
mainly as a solvent and cosolvent.
In oral solutions, glycerin is used as a solvent, sweetening agent, antimicrobial
preservative, and viscosity-increasing agent. It is also used as a plasticizer and in film
coatings. Glycerin is used as a plasticizer of gelatin in the production of soft-gelatin
capsules and gelatin suppositories. Glycerin is employed as a therapeutic agent in a
variety of clinical applications, and is also used as a food additive.
8 Description
Glycerin is a clear, colorless, odorless, viscous, hygroscopic liquid; it has a sweet taste,
approximately 0.6 times as sweet as sucrose.
9 Pharmacopeial Specifications
10. Typical Properties
Boiling point 290oC (with decomposition)
Density 1.2656 g/cm3 at 15oC;
1.2636 g/cm3 at 20oC;
1.2620 g/cm3 at 25oC.
Flash point 176oC (open cup)
Hygroscopicity Hygroscopic.
Melting point 17.8oC
Osmolarity A 2.6% v/v aqueous solution is isoosmotic with serum.
Refractive index
n D15 = 1.4758;
n D20 = 1.4746;
n D25 = 1.4730.
Solubility
.
Specific gravity
Surface tension : 63.4mN/m (63.4 dynes/cm) at 20oC.
Vapor density (relative) : 3.17 (air = 1)
Viscosity (dynamic)
11. Stability and Storage Conditions
Glycerin is hygroscopic. Pure glycerin is not prone to oxidation by the atmosphere under
ordinary storage conditions, but it decomposes on heating with the evolution of toxic
acrolein. Mixtures of glycerin with water, ethanol (95%), and propylene glycol are
chemically stable. Glycerin may crystallize if stored at low temperatures; the crystals do
not melt until warmed to 208C. Glycerin should be stored in an airtight container, in a
cool, dry place.
12 Incompatibilities
Glycerin may explode if mixed with strong oxidizing agents such as chromium trioxide,
potassium chlorate, or potassium permanganate. In dilute solution, the reaction proceeds
at a slower rate with several oxidation products being formed. Black discoloration of
glycerin occurs in the presence of light, or on contact with zinc oxide or basic bismuth
nitrate. An iron contaminant in glycerin is responsible for the darkening in color of
mixtures containing phenols, salicylates, and tannin. Glycerin forms a boric acid
complex, glyceroboric acid, that is a stronger acid than boric acid.
13. Regulatory Status
GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA
Inactive Ingredients Database (dental pastes; buccal preparations; inhalations; injections;
nasal and ophthalmic preparations; oral capsules, solutions, suspensions and tablets; otic,
rectal, topical, transdermal, and vaginal preparations). Included in nonparenteral and
parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable
Non-medicinal Ingredients.
III-C. FORMIC ACID [1]
IUPAC name: Formic acid
Synonyms: formylic acid, hydrogen carboxylic acid,
Methanoic acid, aminic acid, methanoic acid
Other names Aminic acid
Formylic acid
Hydrogen carboxylic acid
Hydroxymethanone
Hydroxy(oxo)methane
Metacarbonoic acid
Oxocarbinic acid
Oxomethanol
Molecular formula CH2O2
Structural Formula
CAS number 64-18-6
Description
Formic acid is a colorless, fuming liquid having a highly pungent, penetrating odor at
room temperature. It is miscible with water and most polar organic solvents, and
somewhat soluble in hydrocarbons. In hydrocarbons and in the vapor phase, it consists of
hydrogen-bonded dimers rather than individual molecules. Owing to its tendency to
hydrogen-bond, gaseous formic acid does not obey the ideal gas law. Solid formic acid
(two polymorphs) consists of an effectively endless network of hydrogen-bonded formic
acid molecules. This relatively complicated compound also forms a low-boiling
azeotrope with water (22.4%) and liquid formic acid also tends to supercool.
Physical and chemical properties Appearance Liquid
Colour Colourless to pale yellow
Odour Pungent
Molar mass 46.03 g mol−1
Solubility Miscible
Boiling point (°c) 107.3
Relative density 1.195 20
Vapour pressure <4.4 kPa 20
pH-value, conc. Solution <1
pH-value, diluted solution 2.2 1
Viscosity 1.57 cP at 26 °C
Flash point (°c) 65
Auto ignition Temperature (°C) 500
Density 1.22 g/mL,
Acidity (pKa) 3.77
Functional Category
Preservative and antibacterial agent
Toxicological information
Toxic dose 1 - LD 50 730 mg/kg (oral rat)
Toxic conc. - LC 50 7.4 mg/l/4h (inh-rat)
Ingestion May cause severe internal injury
Skin contact Causes burns.
Eye contact Causes burns.
Handling and storage
Usage precautions
Avoid contact with skin and eyes. Provide good ventilation. Eliminate all sources of
ignition.
Storage precautions
Keep containers tightly closed. Keep in original container.
Storage class
Corrosive storage.
III-D. DICHLOROMETHANE [1]
IUPAC name Dichloromethane
Synonyms: DCM; Methylene chloride (MC); Methylene dichloride; Methylene
bichloride; Methane dichloride
Other names Methylene chloride, methylene dichloride, Solmethine, Narkotil,
Solaesthin, Di-clo, Freon 30, R-30, DCM, UN 1593, MD
CAS number 75-09-2
Molecular Weight: 84.93
Chemical Formula: CH2Cl2
Structural Formula
Uses
Dichloromethane's volatility and ability to dissolve a wide range of organic compounds
makes it a useful solvent for many chemical processes. Concerns about its health effects
have led to a search for alternatives in many of these applications.
Physical and Chemical Properties
Appearance: Clear, colorless liquid.
Odor: Chloroform-like odor.
Solubility: 1.32 gm/100 gm water @ 20C.
Specific Gravity: 1.318 @ 25C
% Volatiles by volume 100
@ 21C (70F):
Boiling Point: 39.8C (104F)
Melting Point: -97C (-143F)
Vapor Density (Air=1): 2.9
Vapor Pressure (mm Hg): 400 @ 24C (75F)
Handling and Storage
Store in a cool dry well ventilated area. Keep away from heat and flame. Do not get in
eyes, on skin, or on clothing.
REFERENCES: 1. Handbook of Pharmaceutical Excipients Sixth edition By Raymond C Rowe, Paul
J Sheskey and Arian E Quinn. Pharmaceutical Press Publishers
Annexure IV
Experimental Design
The aim of pharmaceutical formulation and development is to develop an acceptable
formulation in the shortest possible time, using minimum number of working hours and
raw materials.
The formula developed by the formulation and development center is first tried at the
pilot scale and then manufacture scale. Only minor changes are to be made during scale-
up. Thus, it is very ideal to study the formulation from all perspectives at laboratory
levels.
In addition to the art of formulation, a statistical technique is available that can aid in the
pharmacist’s choice of formulation components, which can optimize one or more
formulation additives.
A very efficient way to enhance the value of research and to minimize the process
development time is through the experiment. The need of develop this design because
traditional experiments involve a good deal of efforts and time, especially where complex
formulations are to be developed.
The statistical problem solving approach uses a series of small carefully designed
experiments. We sometimes call the statistical approach ‘strategic experimentation’ or
iterative problem solving strategy. We also call this the ‘stop look and listen’ approach to
experimentation. Analyze the results of few experiments and then plan the next
experiments. Any statistical design consist of the small and efficient experiments, namely
a screening experiments where from many factors affecting the process few important
factors are identified, then an optimization experiment where a predictive model is build
for the few factors in the region of optimum and finally a verification experiment where
the results is confirmed at the predicted setting. In the present work factorial design was
used for the development of effective, functional and perfect dosage form. The help of
systematic formulation approach is taken to get detailed knowledge on the formulation.
In the present study, 24, 32and 33 factorial design and Plackett-burman design were used.
Hence, only these designs are discussed in details.
IV-A. FACTORIAL DESIGNS (1-3)
Factorial designs are used in experiments when the effects of different factors or
conditions, on experiment results are to be elucidated. Factorial designs are the design of
choice of simultaneous determination of the effects of several factors and their
interaction. Factors may be qualitative or quantitative. The levels on each factor are the
values or designations assigned to combinations, of all levels, of all factors. The effects
of a factor are the change in response caused by varying the level(s) of the factor.
The important objective of a factorial experimentation is to characterize the effect of
changing the levels of the factor or combination of factors on the response variable.
Predictions based on results of an undersigned experiment will be more variable than
those, which could be obtained in a designed experiment, in particular factorial design.
The optimization procedure is facilitated by construction of an equation that described the
experimental results as a function of the factor levels. A polynomial equation can be
constructed, where the coefficients in the equation are related to the effects and
interaction of the factors. The goal of pharmaceutical formulation is in the shortest
possible time using minimum time and raw materials.
Optimization by experimental design leads to the evolution of a statistically valid model
to understand the relationship between independent and dependent variables.
The equation constructed from 2n factorial experiment is in the following form.
Y=Bo + B1X1+ B2X2+B3X3+B12X1X2+B13X1X3+B23X2X3+B123X1X2X3
Where,
Y= the measured response
Xi= level of ith factor (independent variable)
Bi= the regression coefficient for the ith independent variable
B0= intercept
The magnitudes of the coefficients represent the relative importance of each factor. Once
the polynomial equation has been established, an optimum formulation can be found out
by grid analysis. A computer can calculate the response based on equation at many
combinations of factor levels. The formulation whose response has optimal
characteristics based on the experimenter’s specification is then chosen.
Advantages of Factorial designs:
In absence of interaction, they have maximum efficiency in estimating mail
effects
Maximum use is made of the data, since all main effects and interaction are
calculated from the data
Since factors effects are measured over varying levels of other factors,
conclusions apply to wide range of conditions
Then are orthogonal; all estimated effect and interaction are independent of the
effect of the other factors
If interaction occur; they are necessary to reveal and identify the interaction
More information is obtained with less work
The effects are measured with maximum precision.
Applications of Factorial designs:
It helps and interprets the mechanism of experimental system
It provides guidance for further experiment
It also useful for the drug-excipient compatibility study
It is very useful in an industrial manufacturing operation because it recommends
or implements, a practical procedure or a set of condition
Factorial designs are either full or fractional. Full factorial design is a design in which
every setting of every factor appears with every setting of every other factor is called as a
full factorial design. When experiments are with a large number of factors and/or a large
number of levels for the factors, the number of factors needed to complete factorial
design is also large.
Full Factorial Design:
24 Factorial Design:
A common experimental design is one with all input factors set at two levels each, these
levels are called ‘high’ and ‘low’ or ‘+1’ and ‘-1’, respectively. A design with all possible
high/low combinations of all the input factors is called a full factorial design in two
levels.
In 24 factorial designs four factors and two levels are used to achieve the proper result.
This implies sixteen runs.
The design of is given in Table 1.
Table 1: Design of 24 factorial design
Trial X1 X2 X3 X4
1 -1 -1 -1 -1
2 -1 -1 -1 1
3 -1 -1 1 1
4 -1 1 1 1
5 -1 -1 1 -1
6 -1 1 -1 -1
7 -1 1 1 -1
8 -1 1 -1 1
9 1 -1 -1 -1
10 1 -1 -1 1
11 1 -1 1 1
12 1 1 1 1
13 1 -1 1 -1
14 1 1 -1 -1
15 1 1 1 -1
16 1 1 -1 1
A statistical model incorporating interactive and polynomial terms is used to evaluate the
response. Yi = B0 + B1X1 + B2X2 + B3X3 + B4X4 + B12X1X2 + B13X1X3 + B14X1X4 + B23X2X3 + B24X2X4 + B34X3X4 + B1234X1X2X3X4
Where, Yi is the dependent variable; b0 is the arithmetic mean of the 16 terms; bi is the
estimated coefficient for the factor Xi.
32 Factorial Design:
In 32 full factorial designs two factors and three levels are used. Total 9 trials are made if
this design is employed.
The design of 32 factorial is as given in Table 2.
Table 2: Design of 32 factorial design
Trial X1 X2
1 -1 -1
2 -1 0
3 -1 1
4 0 -1
5 0 0
6 0 1
7 1 -1
8 1 0
9 1 1
A statistical model incorporating interactive and polynomial terms is used to evaluate the
response. Yi = b0 + b1X1 + b2X2 + b11X1
2 + b22X22 + b12X1X2
Where, Yi is the dependent variable; b0 is the arithmetic mean of the 9 terms; bi is the
estimated coefficient for the factor Xi.
33 Factorial Design:
In 33 full factorial designs three factors and three levels are used. Total 27 trials are made
if this design is employed.
The design of 33 factorial is as given in Table 3.
Table 3: Design of 33 factorial design
Trial X1 X2 X3
1 -1 -1 -1
2 -1 -1 0
3 -1 -1 1
4 -1 0 -1
5 -1 0 0
6 -1 0 1
7 -1 1 -1
8 -1 1 0
9 -1 1 1
10 0 -1 -1
11 0 -1 0
12 0 -1 1
13 0 0 -1
14 0 0 0
15 0 0 1
16 0 1 -1
17 0 1 0
18 0 1 1
19 1 -1 -1
20 1 -1 0
21 1 -1 1
22 1 0 -1
23 1 0 0
24 1 0 1
25 1 1 -1
26 1 1 0
27 1 1 1
A statistical model incorporating interactive and polynomial terms is used to evaluate the
responses. Yi = b0 + b1X1 + b2X2 + b3X3 + b11X1
2 + b22X22 + b33X3
2 + b12X1X2 + b23X2X3 + b13X1X3 Where, Yi is the dependent variable; b0 is the arithmetic mean of the 27 terms; bi is the
estimated coefficient for the factor Xi.
IV-B. PLACKETT-BURMAN DESIGN (4-7)
A popular class of screening designs is the Plackett-Burman design (PBD), developed by
R.L. Plackett and J.P. Burman in 1946.It was designed to improve the quality control
process that could be used to study the effects of design parameters on the system state so
that intelligent decisions can be made. Plackett and Burman (PB) devised orthogonal
arrays are useful for screening, which yield unbiased estimates of all main effects in the
smallest design possible. Various number or ‘n’ factors can be screened in an ‘n + 1’ run
PB design.
For the seven factors, the following PBD having eight runs is used for screening.
Batch
no
X1 X2 X3 X4 X5 X6 X7
1 + + + - + - -
2 - + + + - + -
3 - - + + + - +
4 + - - + + + -
5 - + - - + + +
6 + - + - - + +
7 + + - + - - +
8 - - - - - - -
REFERENCES:
1. Bolton S.,Bon C., Pharmaceutical Statistics: Practical and clinical application, 2nd
Ed., Marcel Dekker Inc., NY, 1990:265-280; 506-538
2. Franz R.M., Browne J.E., and Lewis A.R.; Experimental design, modeling, an
optimization strategies for product and process development: In Livermann,
H.A.Riger, M.M.Banker, G.S., Pharmaceutical dosage form: Disperse system
(volume1), Marcel Dekker, NY, 1988: 427-519
3. Lewis, GA, Mathieu D, Phan-Tan-Luu R. Pharmaceutical Experimental Design
Marcel Dekker, NY, 1999: 185-246
4. R. H. Shobha Rani, K.Vanaja. Design of Experiments: Concept and applications
of Plackett-Burman Design: Clinical Research and Regulatory Affairs,
2007,24(1): 1–23
5. Plackett, R. L. & Burman J. P. (1946) Biometrika 33, 305- 325
6. Vander Heyden, Y., Nijhuis, A., Smeyers-Verbeke, J., Vandeginste, B. G. &
Massart, D.L. (2001) J Pharm BiomedAnal 24, 723-753
7. Draper N.R., “Plackett Burman Designs”, Encyclopedia of Statistical Sciences
Volume 6, Ed Johnson Kotz, 9 volumes; Wiley, 1982-1988
Annexure V
Uniformity Index
Uniformity index (UI) is calculated from the data of particle size distribution by using the
following formula.
UI = Dw/Dn
where Dw and Dn are weight average diameter and number average diameter respectively,
and are calculated as follows:
Dw = ∑NiDi4/∑NiDi3
Dn = ∑NiDi/ ∑Ni
where Ni is the number of particles with Di diameter.
As per Shukla et al, values of UI ranging from 1.0 to 1.1 and 1.1 to 1.2 indicate
monodisperse and nearly monodisperse particles. In the present case, values higher than
1.2 have been regarded as indicative of particles with broad particle size distribution.
REFERENCE:
Shukla P G, Kalidhass B, Shah A, Palashkar D V. Preparation and characterization of
microcapsules of water soluble pesticide monocrotophs using polyurethane as carrier
material. J Microencapsul. 2002; 19(3): 293-304
Annexure VI
Desirability Function Approach
The desirability function1,2,3 is one of the most widely used methods in industry for the
optimization of multiple response processes. It is based on the idea that the "quality" of a
product or process that has multiple quality characteristics, with one of them outside of
some "desired" limits, is completely unacceptable.
During optimization, the responses have to be combined in order to produce a product of
desired characteristics. The application of the desirability function combines all the
responses in one measurement and gives the possibility to predict the optimum levels for
the independent variables. The combination of the responses in one desirability function
requires the calculation of the individual functions.
Individual desirability for each response (ID1) is calculated from the following equation.
Q
ID1 = ----------------------
Rmax – Rmin
Q = Rmax – R OR Q = R – Rmin
Where, Q = difference obtained by substracting of an individual response from the
maximum or minimum value of the response
Rmax = maximum value of the response from the all response values
Rmin = minimum value of the response from the all response values
R = value of the response experimentally determined
Similarly individual desirability ID2 and ID3 with respect to other responses are
determined.
Overall desirability (OD) is calculated from the following equation.
OD = (ID1ID2ID3)1/3
The value of OD near to 1 indicates the batch or product having all the different desired
characteristics.
REFERENCES:
1. Swanepoel E, Liebenberg W, Devarakonda B, Villiers M M D. Developing a
discriminatory dissolution test for three mebendazole polymorphs based on solubility
differences. Pharmazie. 2003; 58(2):117–121
2. Sutariya V B, Mashru R C, Sankalia M G, Sankalia J M. Preparation of rapidly
disintegrating tablets of ondansetron hydrochloride by direct compression method
Ars Pharm 2006; 47(3): 293-311
3. Lewis G, Mathieu D, Phan-Than-Luu R. Optimization: Pharmaceutical process
optimization and validation. In Pharmaceutical Experimental Design, 1st Ed;
Swarbrick, James, Boylan, James C., Eds.; Marcel Dekker, Inc.: New York, 1999;
Vol. 92, 265-276
Appendix VII
Acknowledgement This work was funded (Rs.8.675 lac) by All India Council for Technical
Education (AICTE), New Delhi under Research Promotion Scheme vide letter ref.
no. 220-62/FIN/04/05/1333/319 dated 18/04/2007. Title of the project sanctioned
by AICTE is “Preparation and characterization of spherical agglomerates of some
drugs by novel particle engineering technology”.
Publications Review article on Novel particle engineering technology in Drug Discovery
Technology 2006 Dharmesh M. Modi, Megha Barot, Jolly R. Parikh