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Dry, unheated starch is stable if protected from high humidity. When used as a diluent 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.

Incompatibilities

—

Method of Manufacture

Starch is extracted from plant sources through a sequence of processing steps involving coarse milling, repeated water washing, wet sieving, and centrifugal separation. The wet starch obtained from these processes is dried and milled before use in pharmaceutical formulations.

Safety

Starch is widely used as an excipient in pharmaceutical formulations, particularly oral tablets.

Starch is an edible food substance and is generally regarded as an essentially nontoxic and nonirritant material.(23) How- ever, oral consumption of massive doses can be harmful owing the formation of starch calculi, which cause bowel obstruc- tion.(24) Starch may also cause granulomatous reactions when applied to the peritoneum or the meninges. Contamination of surgical wounds with the starch glove powder used by surgeons has also resulted in the development of granulomatous lesions.(25)

Allergic reactions to starch are extremely rare and indivi- duals apparently allergic to one particular starch may not experience adverse effects with a starch from a different botanical source.

LD50 (mouse, IP): 6.6 g/kg(26)

Figure 1: Compression characteristics of corn, potato and wheat starches.

□: Corn starch

⃝: Potato starch

Q: Wheat starch

Tablet machine: Manesty F; speed: 50 per min; weight: 490–510 mg. Strength test: Diametral compression between flat-faced rams. Upper ram stationary, lower moving at 66 mm/s.

Figure 2: Sorption–desorption isotherm of corn starch. Anheuser Busch; Lot #67.

Starch 729

Figure 3: Sorption–desorption isotherm of wheat starch.

⃝: Paygel 55 (Henkel Corp.; Lot #2917D)

Q: Aytex P (Henkel Corp.; Lot #2919D)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and a dust mask are recommended. Excessive dust generation should be avoided to minimize the risks of explosion.

In the UK, the long-term (8-hour TWA) occupational exposure limits for starch are 10 mg/m3 for total inhalable dust and 4 mg/m3 for respirable dust.(27)

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (buccal tablets, oral capsules, powders, suspensions and tablets; topical preparations; and vaginal tablets). Included in nonpar- enteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Amylopectin; a-amylose; maltodextrin; starch, pregelatinized; starch, sterilizable maize.

Amylopectin

CAS number: [9037-22-3]

Comments: amylopectin is a branched D-glucan with mostly

a-D-(1→4) and approximately 4% a-D-(1→6) linkages. The EINECS number for amylopectin is 232-911-6.

a-Amylose

CAS number: [9005-82-7]

Comments: amylose is a linear (1→4)-a-D-glucan.

Comments

Note that corn starch is also known as maize starch and that tapioca starch is also known as cassava starch.

730 Starch

Whereas the USPNF 23 specifies that starch should be produced from corn, potato, tapioca, or wheat, the BP 2004 also permits starch to be produced from rice. In tropical and subtropical countries where these starches may not be readily available, the BP 2004 additionally permits the use of tapioca starch, subject to additional requirements.

Starches from different plant sources differ in their amylose/ amylopectin ratio. For example, corn starch contains about 27% amylose, potato starch about 22%, and tapioca starch about 17%. In contrast, waxy corn starch contains almost entirely amylopectin, with no amylose. These differences modify the physical properties of the starches such that the various types may not be interchangeable in a given pharma- ceutical application. For example, amylose-rich maize starch

has been studied as a potential tablet film-coating ingredi- ent.(28)

Specific References

York P. Studies of the effect of powder moisture content on drug release from hard gelatin capsules. Drug Dev Ind Pharm 1980; 6: 605–627.

Ingram JT, Lowenthal W. Mechanism of action of starch as a tablet disintegrant I: factors that affect the swelling of starch grains at

378. J Pharm Sci 1966; 55: 614–617.

Patel NR, Hopponen RE. Mechanism of action of starch as a disintegrating agent in aspirin tablets. J Pharm Sci 1966; 55: 1065–

1068.

Lowenthal W. Mechanism of action of tablet disintegrants. Pharm Acta Helv 1973; 48: 589–609.

Sakr AM, Kassem AA, Farrag NA. The effect of certain disintegrants on water soluble tablets. Manuf Chem Aerosol News 1973; 44(1): 37–41.

Shangraw RF, Wallace JW, Bowers FM. Morphology and functionality in tablet excipients for direct compression: part II. Pharm Technol 1981; 5(10): 44–60.

Kitamori N, Makino T. Improvement in pressure-dependent dissolution of trepibutone tablets by using intragranular disin- tegrants. Drug Dev Ind Pharm 1982; 8: 125–139.

Rudnic EM, Rhodes CT, Welch S, Bernardo P. Evaluation of the mechanism of disintegrant action. Drug Dev Ind Pharm 1982; 8: 87–109.

Kottke MK, Chueh H-R, Rhodes CT. Comparison of disintegrant and binder activity of three corn starch products. Drug Dev Ind Pharm 1992; 18: 2207–2223.

Faroongsarng D, Peck GE. Swelling and water reuptake of tablets. Part 3. Moisture sorption behavior of tablet disintegrants. Drug Dev Ind Pharm 1994; 20: 779–798.

Illum L, Fisher AN, Jabbal-Gill I, Davis SS. Bioadhesive starch microspheres and absorption enhancing agents act synergistically to enhance the nasal absorption of polypeptides. Int J Pharm 2001; 222: 109–119.

Callens C, Ceulemans J, Ludwig A, et al. Rheological study on mucoadhesivity of some nasal powder formulations. Eur J Pharm Biopharm 2003; 55: 323–328.

Henrist D, Van Bortel L, Lefebvre RA, Remon JP. In vitro and in vivo evaluation of starch-based hot stage extruded double matrix systems. J Control Release 2001; 75: 391–400.

Palviainen P, Heinamaki J, Myllarinen P, et al. Corn starches as film formers in aqueous-based film coating. Pharm Dev Technol 2001; 6: 353–361.

Hauschild K, Picker-Freyer KM. Evaluation of a new coprocessed compound based on lactose and maize starch for tablet formula- tion. AAPS PharmSci 2004; 6:16

Korhonen O, Kanerva H, Vidgren M, et al. Evaluation of novel starch acetate-diltiazem controlled release tablets in healthy human volunteers. J Control Release 2004; 95: 515–520.

Bromberg LE, Buxton DK, Friden PM. Novel periodontal drug delivery systems for treatment of periodontitis. J Control Release 2001; 71: 251–259.

Clausen AE, Bernkop-Schnurch A. Direct compressible poly- methacrylic acid-starch compositions for site-specific drug deliv- ery. J Control Release 2001; 75: 93–102.

Momin M, Pundarikakshundu K. In vitro studies on guar gum based formulation for the colon targeted delivery of Sennosides. J Pharm Pharm Sci 2004; 7: 325–331.

Carr RL. Particle behaviour storage and flow. Br Chem Eng 1970;

15: 1541–1549.

Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 8: 355–369.

Wurster DE, Peck GE, Kildsig DO. A comparison of the moisture adsorption–desorption properties of corn starch, USP, and directly compressible starch. Drug Dev Ind Pharm 1982; 8: 343–354.

Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation Agents: A Handbook of Excipients. New York: Marcel Dekker, 1989: 91–92.

Warshaw AL. Diagnosis of starch peritonitis by paracentesis.

Lancet 1972; ii: 1054–1056.

Michaels L, Shah NS. Dangers of corn starch powder [letter]. Br Med J 1973; 2: 714.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3299.

Health and Safety Executive. EH40/2002: Occupational Exposure Limits 2002. Sudbury: Health and Safety Executive, 2002.

Krogars K, Antikainen O, Heinamaki J, et al. Tablet film-coating with amylose-rich maize starch. Eur J Pharm Sci 2002; 17: 23–30.

Starch, Pregelatinized

Nonproprietary Names

BP: Pregelatinised starch PhEur: Amylum pregelificatum USPNF: Pregelatinized starch

Synonyms

Compressible starch; Instastarch; Lycatab C; Lycatab PGS; Merigel; National 78-1551; Pharma-Gel; Prejel; Sepistab ST 200; Spress B820; Starch 1500 G; Tablitz; Unipure LD; Unipure WG220.

Chemical Name and CAS Registry Number

Pregelatinized starch [9005-25-8]

Empirical Formula and Molecular Weight

(C6H10O5)n where n = 300–1000.

Pregelatinized starch is a starch that has been chemically and/or mechanically processed to rupture all or part of the starch granules and so render the starch flowable and directly compressible. Partially pregelatinized grades are also commer- cially available. Typically, pregelatinized starch contains 5% of free amylose, 15% of free amylopectin, and 80% unmodified starch. The USPNF 23 does not specify the botanical origin of the original starch, but the PhEur 2005 specifies that pregelatinized starch is obtained from maize (corn), potato, or rice starch. See also Starch and Section 13.

Structural Formula

See Starch.

Functional Category

Tablet and capsule diluent; tablet and capsule disintegrant; tablet binder.

Applications in Pharmaceutical Formulation or Technology

Pregelatinized starch is a modified starch used in oral capsule and tablet formulations as a binder, diluent,(1,2) and dis- integrant.(3)

In comparison to starch, grades of pregelatinized starch may be produced with enhanced flow and compression character- istics such that the pregelatinized material may be used as a tablet binder in dry-compression or direct compression processes.(4–14) In such processes, pregelatinized starch is self- lubricating. However, when it is used with other excipients it may be necessary to add a lubricant to a formulation. Although magnesium stearate 0.25% w/w is commonly used for this purpose, concentrations greater than this may have adverse effects on tablet strength and dissolution. Therefore, stearic acid is generally the preferred lubricant with pregelatinized starch.(15)

Pregelatinized starch may also be used in wet granulation processes.(16) See Table I.

Table I: Uses of pregelatinized starch.

Use Concentration (%)

Diluent (hard gelatin capsules) 5–75

Tablet binder (direct compression) 5–20

Tablet binder (wet granulation) 5–10

Tablet disintegrant 5–10

Description

Pregelatinized starch occurs as a moderately coarse to fine, white to off-white colored powder. It is odorless and has a slight characteristic taste.

Examination of fully pregelatinized starch as a slurry in cold water, under a polarizing microscope, reveals no significant ungelatinized granules, i.e., no ‘maltese crosses’ characteristic of the starch birefringence pattern. Examination of samples suspended in glycerin shows characteristic forms depending upon the method of drying used during manufacture: either irregular chunks from drum drying or thin plates. Partially pregelatinized starch (e.g., Starch 1500G and Sepistab ST200) show retention of birefringence patterns typical of unmodified starch granules.

SEM: 1

Excipient: Lycatab PGS Manufacturer: Roquette Fre`res

Pharmacopeial Specifications

See Table II.

732 Starch, Pregelatinized

Table II: Pharmacopeial specifications for pregelatinized starch.

Test PhEur 2005 USPNF 23

Identification + +

pH (10% w/v slurry) 4.5–7.0 4.5–7.0

Iron 420 ppm 40.002%

Oxidizing substances + +

Sulfur dioxide 450 ppm 40.008%

Microbial limits + +

Loss on drying 415.0% 414.0%

Residue on ignition — 40.5%

Foreign matter + —

Sulfated ash 40.6% —

Organic volatile impurities — +

Typical Properties

Acidity/alkalinity: pH = 4.5–7.0 for a 10% w/v aqueous dispersion.

Angle of repose: 40.78 (6) Compressibility: see Starch. Density (bulk): 0.586 g/cm3 Density (tapped): 0.879 g/cm3 Density (true): 1.516 g/cm3

Flowability: 18–23% (Carr compressibility index)(17)

Moisture content: pregelatinized maize starch is hygro- scopic.(14,18,19) See also Figure 1.

Particle size distribution: 30–150 mm, median diameter 52 mm. For partially pregelatinized starch, greater than 90% through a US #100 mesh (149 mm); and less than 0.5% retained on a US #40 mesh (420 mm).

Solubility: practically insoluble in organic solvents. Slightly soluble to soluble in cold water, depending upon the degree of pregelatinization. Pastes can be prepared by sifting the pregelatinized starch into stirred, cold water. Cold-water- soluble matter for partially pregelatinized starch is 10–20%.

Specific surface area:

0.26 m2/g (Colorcon); 0.18–0.28 m2/g (Roquette Ltd).

Viscosity (dynamic): 8–10 mPa s (8–10 cP) for a 2% w/v aqueous dispersion at 258C.

Figure 1: Pregelatinized starch sorption–desorption isotherm.

⃝: Sorption

&: Desorption.

Stability and Storage Conditions

Pregelatinized starch is a stable but hygroscopic material, which should be stored in a well-closed container in a cool, dry place.

Incompatibilities

—

Method of Manufacture

Food-grade pregelatinized starches are prepared by heating an aqueous slurry containing up to 42% w/w of starch at 62–728C. Chemical additives that may be included in the slurry are gelatinization aids (salts or bases) and surfactants, added to control rehydration or minimize stickiness during drying. After heating, the slurry may be spray-dried, roll-dried, extruded, or drum-dried. In the last case, the dried material may be processed to produce a desired particle size range.

Pharmaceutical grades of fully pregelatinized starch use no additives and are prepared by spreading an aqueous suspension of ungelatinized starch on hot drums where gelatinization and subsequent drying takes place. Partially pregelatinized starch is produced by subjecting moistened starch to mechanical pressure. The resultant material is ground and the moisture content is adjusted to specifications.

Safety

Pregelatinized starch and starch are widely used in oral solid- dosage formulations. Pregelatinized starch is generally regarded as a nontoxic and nonirritant excipient. However, oral consumption of large amounts of pregelatinized starch may be harmful.

See Starch for further information.

Handling Precautions

In the UK, the long-term (8-hour TWA) occupational exposure limits for starch are 10 mg/m3 for total inhalable dust and 4 mg/m3 for respirable dust.(20)

Regulatory Status

Included in the FDA Inactive Ingredients Guide (oral capsules, suspensions, and tablets; vaginal preparations). Included in nonparenteral medicines licensed in the UK.

Related Substances

Starch; starch, sterilizable maize.

Comments

A low-moisture grade of pregelatinized starch, Starch 1500 LM (Colorcon), containing less than 7% of water, specifically intended for use as a diluent in capsule formulations is commercially available.(15)

Sepistab ST200 is described as an agglomerate of starch granules consisting of native and pregelatinized corn starch.(21) Compression characteristics of pregelatinized starches from

Starch, Pregelatinized 733

sorghum and plantain have been evaluated against traditional corn-based products.(22)

Specific References

Small LE, Augsburger LL. Aspects of the lubrication requirements for an automatic capsule filling machine. Drug Dev Ind Pharm 1978; 4: 345–372.

Mattson S, Nystro¨ m C. Evaluation of critical binder properties affecting the compactability of binary mixtures. Drug Dev Ind Pharm 2001; 27: 181–194.

Rudnic EM, Rhodes CT, Welch S, Bernardo P. Evaluations of the mechanism of disintegrant action. Drug Dev Ind Pharm 1982; 8: 87–109.

Manudhane KS, Contractor AM, Kim HY, Shangraw RF. Tableting properties of a directly compressible starch. J Pharm Sci 1969; 58: 616–620.

Underwood TW, Cadwallader DE. Influence of various starches on dissolution rate of salicylic acid from tablets. J Pharm Sci 1972; 61: 239–243.

Bolhuis GK, Lerk CF. Comparative evaluation of excipients for direct compression. Pharm Weekbl 1973; 108: 469–481.

Sakr AM, Elsabbagh HM, Emara KM. Sta-Rx 1500 starch: a new vehicle for the direct compression of tablets. Arch Pharm Chem (Sci) 1974; 2: 14–24.

Schwartz JB, Martin ET, Dehner EJ. Intragranular starch: comparison of starch USP and modified cornstarch. J Pharm Sci 1975; 64: 328–332.

Rees JE, Rue PJ. Work required to cause failure of tablets in diametral compression. Drug Dev Ind Pharm 1978; 4: 131–156.

Shangraw RF, Wallace JW, Bowers FM. Morphology and functionality in tablet excipients for direct compression: part II. Pharm Technol 1981; 5(10): 44–60.

Chilamkurti RW, Rhodes CT, Schwartz JB. Some studies on compression properties of tablet matrices using a computerized instrumental press. Drug Dev Ind Pharm 1982; 8: 63–86.

Malamataris S, Goidas P, Dimitriou A. Moisture sorption and tensile strength of some tableted direct compression excipients. Int J Pharm 1991; 68: 51–60.

Iskandarani B, Shiromani PK, Clair JH. Scale-up feasability in high-shear mixers: determination through statistical procedures. Drug Dev Ind Pharm 2001; 27: 651–657.

Shiromani PK, Clair J. Statistical comparison of high-shear versus low-shear granulation using a common formulation. Drug Dev Ind Pharm 2000; 26: 357–364.

Colorcon Technical literature: Starch 1500. 1997.

Jaiyeoba KT, Spring MS. The granulation of ternary mixtures: the effect of the stability of the excipients. J Pharm Pharmacol 1980; 32: 1–5.

Carr RL. Particle behaviour storage and flow. Br Chem Eng 1970;

15: 1541–1549.

Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 8: 355–369.

Wurster DE, Peck GE, Kildsig DO. A comparison of the moisture adsorption–desorption properties of corn starch USP, and directly compressible starch. Drug Dev Ind Pharm 1982; 8: 343–354.

Health and Safety Executive. EH40/2002: Occupational Exposure Limits 2002. Sudbury: Health and Safety Executive, 2002.

Seppic. Technical Literature: Sepistab ST200. 1997.

Alebiowu G, Itiola OA. Compression characteristics of native and pregelatinized forms of sorghum, plantain, and corn starches, and the mechanical properties of their tablets. Drug Dev Ind Pharm 2002; 28(6): 663–672.

General References

Alebiowu G, Itiola OA. The influence of pregelatinized starch disintegrants on interacting variables that act on disintegrant properties. Pharm Tech 2003; 24(8): 28–33.

Monedeero Perales MC, Munoz-Ruiz A, Velasco-Antequera MV, et al. Comparative tableting and microstructural properties of a new starch for direct compression. Drug Dev Ind Pharm 1996; 22: 689–

695.

Rees, JH, Tsardaka KD. Some effects of moisture on the viscoelastic behavior of modified starch during powder compaction. Eur J Pharm Biopharm 1994; 40: 193–197.

Roquette Fre`res. Technical literature: Lycatab PGS. 2001.

Sanghvi PP, Collins CC, Shukla AJ. Evaluation of Preflo modified starches as new direct compression excipients I: tabletting char- acteristics. Pharm Res 1993; 10: 1597–1603.

Starch, Sterilizable Maize

Nonproprietary Names

USP: Absorbable dusting powder

Synonyms

Bio-sorb; double-dressed, white maize starch; Fluidamid R444P; Keoflo ADP; Meritena; modified starch dusting powder; Pure-Dent B851; starch-derivative dusting powder; sterilizable corn starch.

Chemical Name and CAS Registry Number

Sterilizable maize starch

Empirical Formula and Molecular Weight

(C6H10O5)n where n = 300–1000.

Sterilizable maize starch is a modified corn (maize) starch that may also contain up to 2.0% of magnesium oxide.

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