DEPARTEMENT OF PHARMACEUTICS

CHAPTER III
DRUG AND EXCIPIENT PROFILE

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DRUG:ALBENDAZOLE

IUPAC name:

Methyl-[6-(propylthio)-lHbenzoimidazol-2-yl] carbamate.

Figure 2. Molecular structure of ALB

Molecular Formula: C12H15N3O2S, molecular weight 265.34, C 54.32%, H 5.70%, N

15.84%, O 12.06%, S 12.09%

USP/BP/EP name:

USP 40/ Ph. Int: Carbamic acid, [5-(propylthio)-1H-benzimidazol-2-yl]-, methyl ester;

Methyl 5-(propylthio)-2-benzimidazolecarbamate

BP/EP: Methyl [5-(propylsulfanyl)-1H-benzimidazol-2-yl]carbamate

CAS: CAS-54965-21-8

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pKa

4.27 and 9.51

logP

Calculated logP (using BioLoom version 5.0) is 3.46

DESCRIPTION:

ALB occurs as colorless crystals or as a white/almost white powder with a melting point of

208°C–210°C.

Mechanism of Action 1-4

ALB is a member of the benzimidazole group of parasiticidal agents that disrupts parasite

energy metabolism. It specifically causes degenerative alterations in worm cells by binding to

colchicine-sensitive sites of β-tubulin, a constituent cell protein, thus inhibiting its assembly

into microtubulin. The specific action of ALB against parasitic cells rather than mammalian

cells is attributed to its preferential binding to parasitic β-tubulin . It leads to impaired glucose

uptake by the adult and larval forms of the parasites, and eventually depletes glycogen

storage. As a consequence, the production of adenosine trisphosphate decreases because of

insufficient glucose and leads to the death of the parasite . At higher concentrations, ALB

also disrupts parasitic metabolic pathways by inhibiting metabolic enzymes involved in

Krebs cycle, such as malate dehydrogenase and fumarate reductase.

ALB also prevents the formation of the spindle-fiber needed for alignment of chromatin

during cell division, which in turn inhibits cell division, egg production and development, and

hatching of existing eggs. Lack of spindle formation also leads to reduced intracellular

transport and cell motility . Compared to other agents in the benzimidazole group, such as

mebendazole, ALB has a higher activity in a single oral dose of 400 mg against ascariasis,

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hookworm infection, trichostrongylosis, and (to a slightly lesser extent) enterobiasis and

trichuriasis .

Absorption, Distribution, Metabolism, and Excretion7-9

ALB is poorly absorbed from the gastrointestinal tract due to its low aqueous solubility

(Biopharmaceutics Classification System (BCS) class II/IV compound; vide infra). Oral

absorption of ALB in humans is <1–5%. As ALB undergoes rapid first-pass metabolism, its

concentrations are negligible or undetectable in plasma . The sulphoxide is generally

considered to be the active metabolite responsible for ALB’s therapeutic activity. Absorption

and metabolism are rapid, as demonstrated by the peak level of radioactivity after oral

administration of [8] C-ALB and of the intact drug (as sulphoxide) being reached within 2 to

3 hours .

A fatty meal enhances absorption, and a five-fold increase in average plasma concentration of

ALB sulphoxide was achieved when it was co-administered with a fatty mealALB sulphoxide

has a chiral center, and formation of ALB (−) sulphoxide depends on cytochrome P450

enzymes, whereas that of ALB (+) sulphoxide depends on flavin monoxidase. Subsequent

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oxidation to ALB sulphone is mediated by cytochrome P450 isozymes. In humans, ALB (+)

sulphoxide is the predominant form in plasma , with the relative AUCs being 8/9 times that

for the (+)/(−)sulphoxide. Repeated administration of ALB alters its own kinetics, probably

by affecting its metabolic clearance by inducing at least the P450s involved in its own

metabolism.

ALB sulphoxide is 70 percent bound to plasma protein. It is widely distributed throughout the

body, as is evident by its detection in urine, bile, liver, cyst wall, cyst fluid, and cerebrospinal

fluid. Concentrations in plasma are 3 to 10 times and twice higher than in the cyst fluid and

cerebrospinal fluid (simultaneously determined), respectively.

The t1/2el for the parent drug is not reported (low plasma level), while the t1/2el for ALB

sulphoxide is 8 to 12 hours. Urinary excretion of ALB sulphoxide is a minor elimination

pathway, with < 1% of the dose recovered in the urine. Excretion occurs largely in bile, as

evident from the biliary concentration of ALB sulphoxide being similar to that achieved in

plasma. Following 4 weeks of treatment with ALB (200 mg thrice daily), concentrations of

ALB sulphoxide in plasma were approximately 20 percent lower than those observed during

the first half of the treatment period. As mentioned above, the observation suggests that ALB

may induce its own metabolism .

ALB is categorized as Pregnancy Category C, as it has been shown to be teratogenicity (to

cause embryo toxicity and skeletal malformations) in pregnant rats and rabbits . There are no

adequate and well-controlled studies of ALB administration in pregnant women, and it

should only be used during pregnancy if the benefit justifies the potential risk to the foetus .

ALB is excreted in animal milk, but it is not known whether it is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when ALB is

administered to a nursing woman.

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SOLUBILITY PROFILE10-11

Solubility of ALB in water at 37°C is reported to be 1.3 µg/mL .

SOLUBULITY OF ALB fasted state-simulated intestinal fluid is 2.1 µg/ml.

Albendazole (ABZ)

With broad spectrum of activity against human and animal helminth parasites (Alanazi et

al.,2007).

It was first approved for treatment of helminthic infections in sheep in 1977 and

subsequently approved for human use in 1983. In general, most ascariasis, trichuriasis,

enterobiasis and hookworm infections can be successfully treated with single dose ABZ and

strongyloidiasis with multiple doses of ABZ. ABZ has also been used in the treatment of

capillariasis, gnathostomiasis, trichostrongyliasis, hydatidosis, taeniasis, neurocysticercosis,

andthe tissue nematodes cutaneous larval migrans, toxicariasis, trichinosis and filariasis

(incombination with other anthelmintics) (Anupama et al., 2011a).

ABZ is a white to faintly yellowish (USP30-NF25, 2007), odourless powder with poor flow

property. It has a molecular weight of 265.34 g mol-1 and the molecular formula is

C12H15N3O2S. It is a Class II BCS substance, with low solubility and high permeability

(Cavalcanti et al., 2012).

The M.P of ABZ is 209°C and its solubility constant (n-octanol) at

neutral pH is 0.75 ± 0.2 (g/ml) (Castro et al., 2010).

ABZ is practically insoluble in water (Pranzo et al., 2010) and most organic solvents

(ethanol), properties that influence its absorption

and behaviour in the body (El Harti et al., 2014).

It is freely soluble in anhydrous formic acid; very slightly soluble in ether and in methylene

chloride (USP30-NF25, 2007).

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X-ray diffraction revealed that ABZ showed crystalline behaviour and the absence of

polymorphism. Scanning electron microscopy also showed crystals of different sizes and

shapes with a strong tendency to aggregate (Cavalcanti et al., 2012).

Due to their chemical features, all the BZD drugs are sensitive to light, with behaviour

common to all members of this class of compounds. The amine derivative from hydrolysis of

the carbamic group has been reported to be the main photo-degradation product (Yagoub et

al., 2013).

Following storage for one and two months, ABZ expressed noticeable change in assay down

to 85.3 and 74.6%, respectively. It showed high photosensitivity in solution but a reliable

stability in solid form and when exposed to a temperature up to 50 °C. The thermal

degradation test, performed under temperatures from 20 to 50 °C, demonstrated a very high

stability both in solid and solution form. These temperature values were considered a reliable

range that can be reached in the drug storages of the tropical lands. These results confirmed

that the degradation process was caused just by light and not by high temperature (Yagoub et

al., 2013).

Several studies suggest that only limited absorption of BZD anthelmintics are achieved in

cats, dogs and humans, owed mainly to their low dissolution rate on the gastric fluid (Castro

et al.,2010).

The intestinal absorption of ABZ in human has been shown to be < 5% (Fernando et

al.,2011).

After oral administration, ABZ is metabolized rapidly by flavin mono-oxygenases (FMO)

and by the hepatic microsomal cytochrome P450 (CYP) into the chiral metabolite

albendazole sulfoxide [(+)-ABZ-SO; (-)-ABZ-SO)], which possess anthelmintic activity, and

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into the non-chiral metabolite albendazole sulfone (ASON) which lacks pharmacologic

activity (Eslami et al., 2006;Mahler et al., 2008; Marques et al., 2002).

After an oral dose of 400 mg, peak plasma levels of ABZ-SO reach 0.04–0.55 mg/L, with

great variation between individuals (Venkatesan, 1998). ABZ-SO is widely distributed

throughout the body; it is 70% bound to plasma proteins. Clearance of the parent drug is very

rapid in all species but that of the sulphoxide and sulphone metabolites is slower with a half-

life of 8-12 h in man. Excretion occurs very largely as metabolites in bile. Only metabolites

of ABZ are excreted in animals and man, as metabolism is very extensive (Dayan, 2003).

The anthelmintic activity of ABZ has been related to their selective antimitotic activity due to

the preferential binding of these agents to helminthic tubulin over mammalian tubulin

(Vazquez etal., 2003).

It is thought to act by blocking glucose uptake in the larva and adult stage of susceptible

parasites, thereby depleting the energy stores and decreasing formation of ATP leading to

immobilization and death of the parasite (El-Rahman et al., 1999).

ABZ induces the enzymes of the cytochrome P450 system responsible for its metabolism

(Venkatesan, 1998). Increased systemic bioavailability of this drug was reported when the

drug was co-administered.

The low cost and broad spectrum activity of ABZ make it typically the drug of choice for

treatment of several parasitic diseases (Moriwaki et al., 2008). Several studies suggest that

only

limited absorptions are achieved in cats, dogs and humans, owed mainly to their low

dissolution rate on the gastric fluid (Castro et al., 2010).

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This property is a major disadvantage for the use of ABZ in the treatment of systemic

helminthiasis. Furthermore, the lack of water solubility reduces flexibility for formulation

and administration (Alanazi et al., 2007) which is the major problemfor pharmaceutical

formulators to formulate it into solid dosage form. Therefore, to overcome

the problem by improving its dissolution rate is an important goal.

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Povidone[12]

IMAGESOURCE[13]

1. Non-proprietary Names

BP: Povidone; JP: Povidone; PhEur: Povidone; USP: Povidone

2. Synonyms

E1201; Kollidon; Plasdone; Poly[1-(2-oxo-1-pyrrolidinyl)ethylene];Polyvidone;

Polyvinylpyrrolidone; povidonum; Povipharm; PVP; 1-vinyl-2-pyrrolidinone polymer.

3. Functional Category

Disintegrant; dissolution enhancer; suspending agent; tablet binder

4. Molecular weights: K 17 - 10,000; K 30 - 50,000

5. Applications

a)Although povidone is used in a variety of pharmaceutical formulations, it is primarily used

in solid-dosage forms. In tableting, povidone solutions are used as binders in wet-granulation

processes.

b) Povidone is used as a solubilizer in oral and parenteral formulations, and has been shown

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to enhance dissolution of poorly soluble drugs from solid-dosage forms

c) Povidone is additionally used as a suspending, stabilizing, or viscosity-increasing agent in

a number of topical and oral suspensions and solutions

6. Description :-Povidone occurs as a fine, white to creamy-white colored, odorless or almost

odorless, hygroscopic powder. Povidones with K-values equal to or lower than 30 are

manufactured by spray-drying and occur as spheres. Povidone K-90 and higher K-value

povidones are manufactured by drum drying and occur as plates.

7. Typical Properties

Density (bulk) 0.29–0.39 g/cm3

Density (tapped) 0.39–0.54 g/cm3

Melting point Softens at 1508 ºC.

Dynamic viscosity (m Pascals)- 5.5-8.5 (K 28/32) 42

K-value Approximate molecular weight—50,000

8. Stability and Storage Conditions

a) Povidone darkens to some extent on heating at 1508 0C, with a reduction in aqueous

solubility. It is stable to a short cycle of heat exposure around 110–1308 0C; steam

sterilization of an aqueous solution does not alter its properties. Aqueous solutions are

susceptible to mould growth and consequently require the addition of suitable preservatives.

b)Povidone may be stored under ordinary conditions without undergoing decomposition or

degradation. However, since the powder is hygroscopic, it should be stored in an airtight

container in a cool, dry place.

9. Incompatibilities

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Povidone is compatible in solution with a wide range of inorganic salts, natural and synthetic

resins, and other chemicals. It forms molecular adducts in solution with sulfathiazole, sodium

salicylate, salicylic acid, phenobarbital, tannin, and other compounds.

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Lactose, Anhydrous[14]

Image source[15]

1. Synonyms

Anhydrous 60M; Anhydrous Direct Tableting (DT); Anhydrous DT High Velocity;

Anhydrous Impalpable; Lactopress Anhydrous; Lactopress Anhydrous 250; lactosum

anhydricum; lattosio; milk sugar; SuperTab 21AN; SuperTab 22AN; saccharum lactis.

2. Empirical Formula and Molecular Weight

C12H22O11- 342.30

3. Functional Category

Directly compressible tablet excipient; dry powder inhaler carrier; lyophilization aid; tablet

and capsule diluent; tablet and capsule filler.

4. Applications in Pharmaceutical Formulation or Technology

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a)Anhydrous lactose is widely used in direct compression tableting applications, and as a

tablet and capsule filler and binder.

b) Anhydrous lactose can be used with moisture-sensitive drugs due to its low moisture

content. It may also be used in intravenous injections.

5. Description

Anhydrous lactose occurs as white to off-white crystalline particles or powder. Several

different brands of anhydrous lactose are commercially available which contain anhydrous b-

lactose and anhydrous a-lactose. Anhydrous lactose typically contains 70–80% anhydrous b-

lactose and 20–30% anhydrous a-lactose.

6. Typical Properties

a) Brittle fracture index 0.0362

b) Bonding index 0.0049 (at compression pressure 177.8 MPa)(1)

c)Density (true) 1.589 g/cm3 for anhydrous b-lactose 48

d)Density (bulk) 0.71 g/cm3 for Super Tab 21AN. e)

Density (tapped) 0.88 g/cm3 for Super Tab 21AN

7.Stability and Storage Conditions

Mould growth may occur under humid conditions (80% RH and above). Lactose may

develop a brown coloration on storage, the reaction being accelerated by warm, damp

conditions; stored in a well-closed container in a cool, dry place.

8. Incompatibilities

Lactose anhydrous is incompatible with strong oxidizers. When mixtures containing a

hydrophobic leukotriene antagonist and anhydrous lactose or lactose monohydrate were

stored for six weeks at 408C and 75% RH, the mixture containing anhydrous Lactose showed

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greater moisture uptake and drug degradation. Lactose anhydrous is a reducing sugar with the

potential to interact with primary and secondary amines (Millard reaction) when stored under

conditions of high humidity for extended periods.

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Magnesium Stearate[16]

1. Synonyms

Dibasic magnesium stearate; magnesium-distearate; magnesia-stearas; magnesium

octadecanoate; octadecanoic acid, magnesium salt; stearic acid, magnesium salt; Synpro 90.

Image source[17]

2. Functional Category

Tablet and capsule lubricant.

3. 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.

4. Description

Magnesium stearate is a very fine, light white, precipitated or milled, impalpable powder of low bulk

density, having a faint odour of stearic acid and a characteristic taste. The powder is greasy to the

touch and readily adheres to the skin. 49

5.TYPICAL PROPRETIES

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

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Density (true) -- 1.092 g/cm3

Flash point -- 2508 0C

Flowability: Poorly flowing, cohesive powder.

Melting range --117–1508 0C

6. Stability and Storage Conditions

Magnesium stearate is stable and should be stored in a well-closed container in a cool, dry

place.

7. 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.83

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Mannitol[18]

1.Nonproprietary Names

BP:Mannitol,JP:D-mannitol,PhEur:Mannitol,USP-NF:Mannitol

IMAGE SOURCE[19]

2.synonyms

D-Mannitol,Mannitol,69-65-8 mannite,osmitrol,Mannistol,E:421,Manna sugar,compressol

3.Functional Category:

Lypophillization aid plasticizing agent, Sweetning agent; Tablet and Capsule

diluent;Tonicity agent.

4.Description

Mannitol is D-mannitol. It is hexahydric alchol releated to mannose and is isomeric with

Sorbitol.

Mannitol occurs as a white, odourless,crystalline powder or free-flowing granules, it is as

sweet as glucose and half taste as sucrose, and imparts a cooling sensation in mouth.

5. Typical properties

Density(bulk)- 0.430g/m3

Density(tapped)-0.734g/m3

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Density(true)-1.514g/m3

Flash point<1500c

Melting Point-166-1680c

6.Stability and Storage:

Mannitol is stable in dry state and in aqueous solutions,Solutions may be sterilized by

filtration or by autoclaving and if necessary may be autoclaved repeatedly with no adverse

physical or chemical effects, Mannitol doesn’t undergo Maillard reactions. The bulk material

should be stored in a well closed container, and in a cool ,dry place.

7.Applications in Pharmaceutical technology:

a) Mannitol isused as a diluent (10-90%w/w) in tablet formulation.

b) Used in direct-compression tablet

c) Mannitol has been used to prevent thickening in aqueous antacid suspensions of

aluminium hydroxide(<7%w/v)

d) Plasticizer in soft gelatin capsules

e) Mannitol is used as bulking agent in food applications.

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REFERENCES

1.Dollery CT. Albendazole. In: Therapeutic Drugs. Edinburgh: Churchill Livingstone;

1999:A51-A53.

2.Diawara A, Halpenny CM, Churcher TS, et al. Association between Response to

Albendazole Treatment and β-Tubulin Genotype Frequencies in Soil-transmitted Helminths.

PLoS Negl Trop Dis. 2013. doi:10.1371/journal.pntd.0002247

3.Wen H, Zhang HW, Muhmut M, Zou PF, New RRC, Craig PS. Initial observation on

albendazole in combination with cimetidine for the treatment of human cystic

echinococcosis. Ann Trop Med Parasitol. 1994. doi:10.1080/00034983.19 94.11812834

4.Levin S. Therapy of human hydatid disease with mebendazole and albendazole. Infect Dis

Clin Pract. 1993. doi:10.1097/00019048-199311000-00016

5.Morris DL, Dykes PW, Marriner S, et al. Albendazole—Objective Evidence of Response in

Human Hydatid Disease. JAMA J Am Med Assoc. 1985.

doi:10.1001/jama.1985.0335038006902340 6.Albenza (Albendazole) warning and

precautions. https://dailymed.nlm.nih.gov/ dailymed/drugInfo.cfm?setid=e8941166-b77d-

45aa-a6e8-04f1c0afd845.

7.Marriner SE, Morris DL, Dickson B, Bogan JA. Pharmacokinetics of albendazole in man.

Eur J Clin Pharmacol. 1986. doi:10.1007/BF00608219

8.Lange H, Eggers R, Bircher J. Increased systemic availability of albendazole when taken

with a fatty meal. Eur J Clin Pharmacol. 1988. doi:10.1007/ BF00540964

9.Dayan AD. Albendazole, mebendazole and praziquantel. Review of non-clinical toxicity

and pharmacokinetics. In: Acta Tropica. ; 2003. doi:10.1016/S0001- 706X(03)00031-7

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10. Vogt M, Kunath K, Dressman JB. Dissolution improvement of four poorly water soluble

drugs by cogrinding with commonly used excipients. Eur J Pharm Biopharm. 2008.

doi:10.1016/j.ejpb.2007.05.009.

11. Vogt M, Kunath K, Dressman JB. Dissolution improvement of four poorly water soluble

drugs by cogrinding with commonly used excipients. Eur J Pharm Biopharm. 2008.

doi:10.1016/j.ejpb.2007.05.009.

12. Rowe et al., eds. Handbook of Pharmaceutical Excipients, 5th edn. London:

Pharmaceutical Press, 2012.pg:611-616

13.WIKIPEDIA

14. Rowe et al., eds. Handbook of Pharmaceutical Excipients, 5th edn. London:

Pharmaceutical Press, 2012.pg:737

15.WIKIPEDIA

16. Rowe et al., eds. Handbook of Pharmaceutical Excipients, 5th edn. London:

Pharmaceutical Press, 2012.pg:1122-1131

17.WIKIPEDIA

18. Rowe et al., eds. Handbook of Pharmaceutical Excipients, 7th edn. London:

Pharmaceutical Press, 2012.pg:479-482

19.WIKIPEDIA

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