Povidone

Nonproprietary Names

BP: Povidone JP: Povidone

PhEur: Povidonum USP: Povidone

Synonyms

E1201; Kollidon; Plasdone; poly[1-(2-oxo-1-pyrrolidinyl)ethy- lene]; polyvidone; polyvinylpyrrolidone; PVP; 1-vinyl-2-pyrro- lidinone polymer.

Chemical Name and CAS Registry Number

Ethenyl-2-pyrrolidinone homopolymer [9003-39-8]

Empirical Formula and Molecular Weight

(C6H9NO)n 2500–3 000 000

The USP 28 describes povidone as a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, the differing degree of polymerization of which results in polymers of various molecular weights. It is characterized by its viscosity in aqueous solution, relative to that of water, expressed as a K-value, in the range 10–120. The K-value is calculated using Fikentscher’s equation:(1)

 

where z is the relative viscosity of the solution of concentration

c (in % w/v), and k is the K-value × 10–3.

Alternatively, the K-value may be determined from the following equation:

 

where z is the relative viscosity of the solution of concentration

c (in % w/v).

Approximate molecular weights for different povidone grades are shown in Table I.

Table I: Approximate molecular weights for different grades of povidone.

 

K-value Approximate molecular weight    

12 2 500    

15 8 000    

17 10 000    

25 30 000    

30 50 000    

60 400 000    

90 1 000 000    

120 3 000 000  

See also Section 8.

Structural Formula

 

Functional Category

Disintegrant; dissolution aid; suspending agent; tablet binder.

Applications in Pharmaceutical Formulation or Technology

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.(2,3) Povidone is also added to powder blends in the dry form and granulated in situ by the addition of water, alcohol, or hydroalcoholic solutions. Povidone is used as a solubilizer in oral and parenteral formulations and has been shown to enhance dissolution of poorly soluble drugs from solid-dosage forms.(4–6) Povidone solutions may also be used as coating agents.

Povidone is additionally used as a suspending, stabilizing, or viscosity-increasing agent in a number of topical and oral suspensions and solutions. The solubility of a number of poorly soluble active drugs may be increased by mixing with povidone. See Table II.

Special grades of pyrogen-free povidone are available and have been used in parenteral formulations; see Section 14.

Table II: Uses of povidone.

Use Concentration (%)

Carrier for drugs 10–25

Dispersing agent Up to 5

Eye drops 2–10

Suspending agent Up to 5

Tablet binder, tablet diluent, or coating agent 0.5–5

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.

Pharmacopeial Specifications

See Table III.

612 Povidone

 Table III: Pharmacopeial specifications for povidone.

 

Test JP 2001 PhEur 2005 USP 28    

Identification + + +    

Characters — + —    

pH — + 3.0–7.0    

K 4 30 3.0–5.0 3.0–5.0 —    

K > 30 4.0–7.0 4.0–7.0 —    

Appearance of solution + + —    

Viscosity — + —    

Water 45.0% 45.0% 45.0%    

Residue on ignition 40.1% 40.1% 40.1%    

Lead — — 410 ppm    

Aldehydes 4500 ppm(a) 4500 ppm(a) 40.05%    

Hydrazine 41 ppm 41 ppm 41 ppm    

Vinylpyrrolidinone 410 ppm 410 ppm 40.2%    

Peroxides 4400 ppm(b) 4400 ppm(b) —    

K-value 25–90 — 10–120    

415 90.0–108.0% 85.0–115.0% 85.0–115.0%    

>15 90.0–108.0% 90.0–108.0% 90.0–108.0%    

Heavy metals 410 ppm 410 ppm —    

Assay (nitrogen content) 11.5–12.8% 11.5–12.8% 11.5–12.8%  

(a) Expressed as acetaldehyde.

(b) Expressed as hydrogen peroxide.

Typical Properties

Acidity/alkalinity: pH = 3.0–7.0 (5% w/v aqueous solution).

Density (bulk): 0.29–0.39 g/cm3 for Plasdone.



Figure 2: Sorption–desorption isotherm of povidone K-29/32 (Plasdone K-29/32).

Particle size distribution:

Kollidon 25/30: 90% >50 mm, 50% >100 mm, 5%

Density (tapped): 0.39–0.54 g/cm3 for Plasdone.

Density (true): 1.180 g/cm3

>200 mm;

Kollidon 90: 90% >200 mm, 95% >250 mm.



(7)

Flowability:

20 g/s for povidone K-15;

16 g/s for povidone K-29/32.

Melting point: softens at 1508C.

Moisture content: povidone is very hygroscopic, significant amounts of moisture being absorbed at low relative humidities. See Figures 1 and 2.

 

Figure 1: Sorption–desorption isotherm of povidone K-15 (Plasdone K-15).

Solubility: freely soluble in acids, chloroform, ethanol (95%), ketones, methanol, and water; practically insoluble in ether, hydrocarbons, and mineral oil. In water, the concentration of a solution is limited only by the viscosity of the resulting solution, which is a function of the K-value.

Viscosity (dynamic): the viscosity of aqueous povidone solu- tions depends on both the concentration and the molecular weight of the polymer employed. See Tables IV and V.(7)

Table IV: Dynamic viscosity of 10% w/v aqueous povidone (Kollidon) solutions at 208C.(7)

 

Grade Dynamic viscosity (mPa s)    

K-11/14 1.3–2.3    

K-16/18 1.5–3.5    

K-24/27 3.5–5.5    

K-28/32 5.5–8.5    

K-85/95 300–700  

Table V: Dynamic viscosity of 5% w/v povidone (Kollidon) solutions in ethanol (95%) and propan-2-ol at 258C.(7)

 

Grade Dynamic viscosity (mPa s)    

Ethanol (95%) Propan-2-ol    

K-12PF 1.4 2.7    

K-17PF 1.9 3.1    

K-25 2.7 4.7    

K-30 3.4 5.8    

K-90 53.0 90.0  

Povidone 613

SEM: 1

Excipient: Povidone K-15 (Plasdone K-15) Manufacturer: ISP

Lot No.: 82A-1

Magnification: 60×

Voltage: 5 kV

 

SEM: 2

Excipient: Povidone K-15 (Plasdone K-15) Manufacturer: ISP

Lot No.: 82A-1

Magnification: 600×

Voltage: 5 kV



SEM: 3

Excipient: Povidone K-26/28 (Plasdone K-26/28) Manufacturer: ISP

Lot No.: 82A-2

Magnification: 60×

Voltage: 5 kV

 

SEM: 4

Excipient: Povidone K-26/28 (Plasdone K-26/28) Manufacturer: ISP

Lot No.: 82A-2

Magnification: 600×

Voltage: 10 kV

   

614 Povidone

SEM: 5

Excipient: Povidone K-30 (Plasdone K-30) Manufacturer: ISP

Lot No.: 82A-4

Magnification: 60×

Voltage: 10 kV

 

SEM: 6

Excipient: Povidone K-30 (Plasdone K-30) Manufacturer: ISP

Lot No.: 82A-4

Magnification: 600×

Voltage: 10 kV

 

SEM: 7

Excipient: Povidone K-29/32 (Plasdone K-29/32) Manufacturer: ISP

Lot No.: 82A-3

Magnification: 60×

Voltage: 5 kV

 

SEM: 8

Excipient: Povidone K-29/32 (Plasdone K-29/32) Manufacturer: ISP

Lot No.: 82A-3

Magnification: 600×

Voltage: 10 kV

 

Stability and Storage Conditions

Povidone darkens to some extent on heating at 1508C, with a reduction in aqueous solubility. It is stable to a short cycle of heat exposure around 110–1308C; steam sterilization of an

Povidone 615

aqueous solution does not alter its properties. Aqueous solutions are susceptible to mold growth and consequently require the addition of suitable preservatives.

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.

Incompatibilities

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; see Section 18. The efficacy of some preservatives, e.g. thimerosal, may be adversely affected by the formation of complexes with povidone.

Method of Manufacture

Povidone is manufactured by the Reppe process. Acetylene and formaldehyde are reacted in the presence of a highly active copper acetylide catalyst to form butynediol, which is hydro- genated to butanediol and then cyclodehydrogenated to form butyrolactone. Pyrrolidone is produced by reacting butyrolac- tone with ammonia. This is followed by a vinylation reaction in which pyrrolidone and acetylene are reacted under pressure. The monomer, vinylpyrrolidone, is then polymerized in the presence of a combination of catalysts to produce povidone.

Safety

Povidone has been used in pharmaceutical formulations for many years, being first used in the 1940s as a plasma expander, although it has now been superseded for this purpose by dextran.(8)

Povidone is widely used as an excipient, particularly in oral tablets and solutions. When consumed orally, povidone may be regarded as essentially nontoxic since it is not absorbed from the gastrointestinal tract or mucous membranes.(8) Povidone additionally has no irritant effect on the skin and causes no sensitization.

Reports of adverse reactions to povidone primarily concern the formation of subcutaneous granulomas at the injection site of intramuscular injections formulated with povidone.(9) Evidence also exists that povidone may accumulate in the organs of the body following intramuscular injection.(10)

A temporary acceptable daily intake for povidone has been set by the WHO at up to 25 mg/kg body-weight.(11)

LD50 (mouse, IP): 12 g/kg(12)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, gloves, and a dust mask are recommended.

Regulatory Status

Accepted for use in Europe as a food additive. Included in the FDA Inactive Ingredients Guide (IM and IV injections; ophthalmic preparations; oral capsules, drops, granules, suspensions, and tablets; sublingual tablets; topical and vaginal preparations). Included in nonparenteral medicines licensed in



the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Crospovidone.

Comments

The molecular adduct formation properties of povidone may be used advantageously in solutions, slow-release solid-dosage forms, and parenteral formulations. Perhaps the best-known example of povidone complex formation is povidone–iodine, which is used as a topical disinfectant.

For accurate standardization of solutions, the water content of the solid povidone must be determined before use and taken into account for any calculations. A specification for povidone is contained in the Food Chemicals Codex (FCC).

Specific References

Fikentscher H, Herrle K. Polyvinylpyrrolidone. Modern Plastics

1945; 23(3): 157–161, 212, 214, 216, 218.

Becker D, Rigassi T, Bauer-Brandl A. Effectiveness of binders in wet granulation: comparison using model formulations of different tabletability. Drug Dev Ind Pharm 1997; 23(8): 791–808.

Stubberud L, Arwidsson HG, Hjortsberg V, Graffner C. Water– solid interactions. Part 3. Effect of glass transition temperature, Tg and processing on tensile strength of compacts of lactose and lactose/polyvinyl pyrrolidone. Pharm Dev Technol 1996; 1(2): 195–204.

Iwata M, Ueda H. Dissolution properties of glibenclamide in combinations with polyvinylpyrrolidone. Drug Dev Ind Pharm 1996; 22: 1161–1165.

Lu WG, Zhang Y, Xiong QM, et al. Development of nifedipine (NE) pellets with a high bioavailability. Chin Pharm J Zhongguo Yaoxue Zazhi 1995; 30(Nov Suppl): 24–26.

Chowdary KP, Ramesh KV. Microencapsulation of solid disper- sions of nifedipine-novel approach for controlling drug release. Indian Drugs 1995; 32(Oct): 477–483.

BASF Corporation. Technical literature: Soluble Kollidon Grades, Soluble Polyvinylpyrrolidone for the Pharmaceutical Industry, 1997.

Wessel W, Schoog M, Winkler E. Polyvinylpyrrolidone (PVP), its diagnostic, therapeutic and technical application and consequences thereof. Arzneimittelforschung 1971; 21: 1468–1482.

Hizawa K, Otsuka H, Inaba H, et al. Subcutaneous pseudosarco- matous polyvinylpyrrolidone granuloma. Am J Surg Pathol 1984; 8: 393–398.

Christensen M, Johansen P, Hau C. Storage of polyvinylpyrroli- done (PVP) in tissues following long-term treatment with a PVP containing vasopressin preparation. Acta Med Scand 1978; 204: 295–298.

FAO/WHO. Evaluation of certain food additives and contami- nants. Twenty-seventh report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1983; No. 696.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3016–3017.

General References

Adeyeye CM, Barabas E. Povidone. In: Brittain HG, ed. Analytical Profiles of Drug Substances and Excipients, vol. 22. London: Academic Press, 1993: 555–685.

Genovesi A, Spadoni A, Funaro C, Vecchio C. Binder evaluation in tabletting. Manuf Chem 2004; 175(6): 29–30.

Horn D, Ditter W. Chromatographic study of interactions between polyvinylpyrrolidone and drugs. J Pharm Sci 1982; 71: 1021–1026.

616 Povidone

Hsiao CH, Rhodes HJ, Blake MI. Fluorescent probe study of sulfonamide binding to povidone. J Pharm Sci 1977; 66: 1157– 1159.

ISP. Technical literature: Plasdone povidone USP, 1999.

Jager KF, Bauer KH. Polymer blends from PVP as a means to optimize properties of fluidized bed granulates and tablets. Acta Pharm Technol 1984; 30(1): 85–92.

Plaizier-Vercammen JA, DeNe`ve RE. Interaction of povidone with aromatic compounds III: thermodynamics of the binding equilibria and interaction forces in buffer solutions at varying pH values and varying dielectric constant. J Pharm Sci 1982; 71: 552–556.

Robinson BV, Sullivan FM, Borzelleca JF, Schwartz SL. PVP: A Critical Review of the Kinetics and Toxicology of Polyvinylpyrrolidone (Povidone). Chelsea, MI: Lewis Publishers, 1990.

Shefter E, Cheng KC. Drug–polyvinylpyrrolidone (PVP) dispersions. A differential scanning calorimetric study. Int J Pharm 1980; 6: 179– 182.

Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients.

Boca Raton, FL: CRC Press, 1992: 303–305.

Authors

AH Kibbe.

Date of Revision

30 August 2005.

Propionic Acid

Nonproprietary Names

USPNF: Propionic acid

Synonyms

Carboxyethane; ethanecarboxylic acid; E280; ethylformic acid; metacetonic acid; methylacetic acid; propanoic acid; pseudo- acetic acid.

Chemical Name and CAS Registry Number

Propionic acid [79-09-4]

Empirical Formula and Molecular Weight

C3H6O2 74.08

Structural Formula

 

Functional Category

Acidifying agent; antimicrobial preservative; antioxidant; esterifying agent.

Applications in Pharmaceutical Formulation or Technology

Propionic acid is primarily used as an antioxidant and antimicrobial preservative in foods, and in oral and topical pharmaceutical applications. It is also used as an esterifying agent.

Description

Propionic acid occurs as a corrosive, oily liquid having a slightly pungent, disagreeable, rancid odor. It is flammable.