med 5

Applications in Pharmaceutical Formulation or Technology

Sulfuric acid is used as an acidifying agent in a variety of pharmaceutical and food preparations. It may also be used to prepare dilute sulfuric acid, which, in addition to its use as an excipient, has some therapeutic use for the treatment of gastric hypoacidity, as an astringent in diarrhea, or to stimulate appetite. Sulfuric acid has been used in parenteral, oral, topical, and ophthalmic pharmaceutical formulations.

Description

Sulfuric acid occurs as a clear, colorless, odorless, oily liquid. It is very corrosive and has a great affinity for water.

The USPNF 23 specifies that sulfuric acid contains not less than 95% and not more than 98%, by weight, of H2SO4; the remainder is water. See also Section 9.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for sulfuric acid.

Test PhEur 2005 USPNF 23

Identification + +

Appearance of solution + —

Residue on ignition — 40.005%

Chloride 450 ppm 40.005%

Arsenic 41 ppm 41 ppm

Heavy metals 45 ppm 45 ppm

Weight per mL ≈1.84 —

Iron 425 ppm —

Nitrate + —

Reducing substances — +

Assay (of H2SO4) 95.0–100.5% 95.0–98.0%

Typical Properties

Boiling point:

≈2908C for H2SO4 (95%–98% w/w); 3308C for H2SO4 (100% w/w).

Density: ≈1.84 g/cm3 at 208C

Dissociation constant:

pKa1 = —3.00;

pKa2 = 1.99.

Freezing point:

108C for H2SO4 (100% w/w);

38C for H2SO4 (98% w/w);

—328C for H2SO4 (93% w/w).

Solubility: miscible with ethanol and water.

Vapor density: 3.4 (air = 1.0)

Vapor pressure: <0.3 mmHg at 208C

Stability and Storage Conditions

Sulfuric acid is stable but very corrosive and hygroscopic. It will draw moisture from the atmosphere. Sulfuric acid should be stored in a tightly closed container in an explosion-proof area. Containers should be stored out of direct sunlight and away from heat. Avoid heat and moisture. Isolate from incompatible materials. See also Section 12.

Incompatibilities

Avoid storage in close proximity to water, most common metals, organic materials, strong reducing agents, combustible materials, strong bases, carbonates, sulfides, cyanides, strong oxidizing agents, and carbides.

Sulfuric acid is a powerful oxidizer and may ignite or explode on contact with many materials.

It can react violently with the evolution of a large amount of heat. Oxides of sulfur and hydrogen can be generated during reactions.

Great care must be exercised when mixing with other liquids.

Sulfuric Acid 759

Method of Manufacture

Sulfuric acid may be prepared industrially by either the contact process or the chamber process.(1,2)

NO2 + SO2 + H2O → H2SO4 + NO

Safety

Sulfuric acid is widely used in a variety of pharmaceutical formulations. Although concentrated sulfuric acid is very corrosive, it is normally used well diluted in formulations. Concentrated sulfuric acid will react violently with water and much heat is generated. When diluting sulfuric acid, the acid should always be added to the other liquid with great caution. The concentrated solution is extremely corrosive and can cause severe damage or necrosis on contact with the eyes and skin. Ingestion may cause severe injury or death. Inhalation of

concentrated vapors can cause serious lung damage.

LD50 (rat, oral): 2.14 g/kg(3)

Handling Precautions

Caution should be exercised when handling sulfuric acid and suitable protection against inhalation and spillage should be made. Respiratory protection may not be required where adequate ventilation exists. Eye protection (safety goggles and face shield), rubber gloves, and apron are recommended, depending on the circumstances and quantity of sulfuric acid handled. Do not dilute spills of concentrated acid with water since an exothermic reaction will occur. Spills should be neutralized with soda ash or lime. Splashes on the skin and eyes should be treated by immediate and prolonged washing with large amounts of water followed by the application of sodium bicarbonate and medical attention should be sought.

Fumes can cause irritation or permanent damage to the eyes, nose, and respiratory system; prolonged exposure to fumes may damage the lungs.

In the UK, the long-term exposure limit (8-hour TWA) for sulfuric acid is 1 mg/m3.(4,5)

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (IM, IV, and IP injections, inhalation solutions, irrigation solutions, nasal, ophthalmic solutions and suspensions, oral solutions, and topical emulsions and creams). Included in nonparenteral and

parenteral medicines licensed in Europe. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Dilute sulfuric acid; fuming sulfuric acid.

Dilute sulfuric acid

Density: 1.062–1.072 g/cm3

Comments: prepared by adding 104 g of sulfuric acid to 896 g of purified water with constant stirring and cooling. Dilute sulfuric acid contains between 9.5% and 10.5% w/w of H2SO4.

Fuming sulfuric acid

Synonyms: oleum.

Comments: fuming sulfuric acid consists of H2SO4 with free sulfur trioxide (SO3). It is prepared by adding sulfur trioxide to sulfuric acid. Available in grades containing up to about 80% free SO3.

Fuming sulfuric acid is a colorless or slightly colored, viscous liquid that emits choking fumes of sulfur trioxide. It is extremely corrosive and should be handled with great care and stored in tightly closed glass-stoppered bottles.

Comments

A specification for sulfuric acid is contained in the Food Chemicals Codex (FCC). The EINECS number for sulfuric acid is 231-639-5.

Specific References

Druecker WW, West JR. The Manufacture of Sulfuric Acid. New York: Reinhold, 1959: 515.

Nickless G, ed. Inorganic Sulphur Chemistry. New York: Elsevier, 1968: 535–561.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3331–3332.

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

Health and Safety Executive. EH40/2002: Occupational Exposure Limits 2002 Supplement 2003. Sudbury: Health and Safety Executive, 2003.

BP: Sunflower oil, refined

PhEur: Helianthi annui oleum raffinatum

Synonyms

Huile de tournesol; oleum helianthi; sunflowerseed oil.

Chemical Name and CAS Registry Number

Sunflower oil [8001-21-6]

Empirical Formula and Molecular Weight

See Section 5.

Structural Formula

Sunflower oil is classified as an oleic–linoleic acid oil. Its composition includes linoleic acid (66%), oleic acid (21.3%), palmitic acid (6.4%), arachidic acid (4.0%), stearic acid (1.3%), and behenic acid (0.8%).

The PhEur 2005 describes sunflower oil as the refined fatty oil obtained from the seeds of Helianthus annus C. by mechanical expression or by extraction. A suitable antioxidant may be added.

Functional Category

Diluent; emollient; emulsifying agent; solvent; tablet binder.

Applications in Pharmaceutical Formulation or Technology

Sunflower oil is widely used as an edible oil, primarily in oleomargarine. It is also used extensively in cosmetics and pharmaceutical formulations.

Therapeutically, sunflower oil is used to provide energy and essential fatty acids for parenteral nutrition. Studies have shown that sunflower oil may be used in intramuscular injections without inducing tissue damage.(1)

Description

Sunflower oil occurs as a clear, light yellow-colored liquid with a bland, agreeable taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for sunflower oil.

Unsaponifiable matter 41.5%

Alkaline impurities +

Composition of fatty acids +

Palmitic acid 4.0–9.0%

Stearic acid 1.0–7.0%

Oleic acid 14.0–40.0%

Linoleic acid 48.0–74.0%

Typical Properties

Boiling point: 40–608C

Density: 0.915–0.919

Hydroxyl value: 14–16

Iodine number: 125–140 Melting point: —188C Refractive index:

n25 = 1.472–1.474;

n40 = 1.466–1.468.

Saponification number: 188–194

Solubility: miscible with benzene, chloroform, carbon tetra- chloride, diethyl ether, and light petroleum; practically insoluble in ethanol (95%) and water.

Stability and Storage Conditions

Sunflower oil should be stored in an airtight, well-filled container, protected from light. Stability may be improved by the addition of an antioxidant such as butylated hydroxy- toluene.

Incompatibilities

The oxidative stability of sunflower oil is reduced in the presence of iron oxides and zinc oxide.(2)

Sunflower oil forms a ‘skin’ after being exposed to air for 2–3 weeks.

Method of Manufacture

Sunflower oil is obtained from the fruits and seeds (achenes) of the sunflower, Helianthus annus (Compositae), by mechanical means or by extraction.

Safety

Sunflower oil is widely used in food products and on its own as an edible oil. It is also used extensively in cosmetics and topical pharmaceutical formulations and is generally regarded as a relatively nontoxic and nonirritant material.

Sunflower Oil 761

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. When heated to decomposi- tion, sunflower oil emits acrid smoke and irritating fumes.

Regulatory Status

GRAS listed. Included in nonparenteral medicines licensed in the UK.

Related Substances

Corn oil; cottonseed oil; peanut oil; sesame oil; soybean oil.

Comments

High oleic acid content sunflower oil with good oxidative stability and emollient properties is commercially available for use in cosmetic formulations.(3) Sunflower oil with marked oxidative stability is particularly suitable for the manufacture of sunscreen agents.(4)

Sunflower oil should be labeled to indicate the name and concentration of any antioxidant added, and also whether the oil was obtained by mechanical expression or extraction. A specification for sunflower oil is contained in the Food Chemicals Codex (FCC).

The EINECS number for sunflower oil is 232-273-9.

Specific References

Vinardell MP, Vives MA. Plasma creatine kinase activity after intramuscular injection of oily vehicles in rabbits. Pharm Pharmacol Lett 1996; 6(2): 54–55.

Brown JH, Arquette DJ, Kleiman R, et al. Oxidative stability of botanical emollients. Cosmet Toilet 1997; 112(7): 87–90, 92, 94,

96–98.

Arquette DJ, Cummings M, Dwyer K, et al. A natural oil made to last. Cosmet Toilet 1997; 112(1): 67–72.

Arquette DJ, Brown J, Dwyer K, Reinhardt J. Oils and fats: place in the sun. Soap Perfum Cosmet 1994; 67(Nov): 49, 51.

Suppository Bases, Hard Fat

Nonproprietary Names

BP: Hard fat

PhEur: Adeps solidus USPNF: Hard fat

Synonyms

Adeps neutralis; Akosoft; Akosol; Cremao CS-34; Cremao CS- 36; hydrogenated vegetable glycerides; Massa estarinum; Massupol; Novata; semisynthetic glycerides; Suppocire; Weco- bee; Witepsol.

Chemical Name and CAS Registry Number

Hard fat triglyceride esters

Empirical Formula and Molecular Weight

Hard fat suppository bases consist mainly of mixtures of the triglyceride esters of the higher saturated fatty acids (C8H17COOH to C18H37COOH) along with varying propor- tions of mono- and diglycerides. Special grades may contain additives such as beeswax, lecithin, polysorbates, ethoxylated fatty alcohols, and ethoxylated partial fatty glycerides.

Structural Formula

where R = H or OC(CH2)nCH3; n = 7–17 Not all Rs can be H at the same time.

Functional Category

Suppository base.

Applications in Pharmaceutical Formulation or Technology

The primary application of hard fat suppository bases, or semisynthetic glycerides, is as a vehicle for the rectal or vaginal administration of a variety of drugs, either to exert local effects or to achieve systemic absorption.

Selection of a suppository base cannot usually be made in the absence of knowledge of the physicochemical properties and intrinsic thermodynamic activity of the drug substance. Other drug-related factors that can affect release and absorp- tion and which must therefore be considered are the particle

size distribution of insoluble solids, the oil : water partition coefficient, and the dissociation constant. The displacement value should also be known, as well as the ratio of drug to base. Properties of the suppository base that may or may not be modified by the drug, or that can influence drug release, are the melting characteristics, chemical reactivity, and rheology. The presence of additives in the base can also affect performance.

Melting characteristics Fatty-based suppositories intended for systemic use should liquefy at just below body temperature. Softening or dispersion may be adequate for suppositories intended for local action or modified release. High-melting- point bases may be indicated for fat-soluble drugs that tend to depress the melting point of bases or for suppositories used in warm climates. Drugs that dissolve in bases when hot may create problems if they deposit as crystals of different form or increased size on cooling or on storage. Low-melting-point bases, particularly those that melt to liquids of low viscosity, can be of value when large volumes of insoluble substances are to be incorporated; there is a risk of sedimentation in such instances. An important factor during processing is the time required for setting. This is affected by the temperature difference between the melting point and the solidification point.(1,2)

Chemical reactivity Although the use of bases with low hydr- oxyl values (low partial ester content) is indicated to minimize the risk of interaction with chemically reactive compounds, formulators should be aware that hydroxyl values are also related to hydrophilic properties, which, in turn, can modify both release and absorption rates. Bases with low hydroxyl values tend to be less plastic than those with higher values and, if cooled rapidly, may become excessively brittle. Per- oxide values give a measure of the resistance of the base to oxidation and are a guide to the onset of rancidity.

Rheology The viscosity of the melted base can affect the uni- formity of distribution of suspended solids during manufac- ture. It can also influence the release and absorption of the drug in the rectum. Further reduction in the particle size of insoluble solids is the method of choice to minimize the risk of sedimentation. However, the presence of a high content of fine, suspended particles is likely to increase viscosity. It may also make pouring difficult, delay melting, and induce brittle- ness on solidification. Additives are sometimes included to modify rheological properties and to maintain homogeneity,

e.g. microcrystalline wax, but the extent of their effect on drug release should first be assessed. Release from a base in which viscosity has been enhanced by an added thickener may vary and be related to the aqueous solubility of the drug itself.

Additives Some grades of commercial bases already contain additives, and these are usually identified by the manufac- turers by means of suitable letters and numbers. Additives may also be incorporated by formulators. Properties of sup- positories that have been modified and additives or types of additives that have been used are shown in Table I. Water is undesirable as an additive because it enhances hydrolysis and

Suppository Bases, Hard Fat 763

the potential for a chemical reaction between constituents of the suppository. In low concentration, water plays little part in drug release and can serve as a medium for microbial growth.

Table I: Selected suppository additives.

Property Additive

0.950–0.980 g/cm3 for Witepsol at 208C.

Heat of melting (22–408C):

≈145 J/g/8C for Massa estarinum; 100–130 J/g/8C for Suppocire;

≈145 J/g/8C for Witepsol. Hydroxyl value: see Table III. Iodine value: see Table III. Melting point: see Table III.

Dispersants (release and/or absorption Surfactants enhancers)

Moisture content:

40.2% w/w for Massa estarinum;

Hygroscopicity (reduced) Colloidal silicon dioxide Hardeners (or increasing melting point) Beeswax

Cetyl alcohol Stearic acid Stearyl alcohol

Aluminum monostearate (or di- and tristearate)

Bentonite Magnesium stearate

Colloidal silicon dioxide Plasticizers (or decreasing melting point) Glyceryl monostearate

Myristyl alcohol Polysorbate 80 Propylene glycol

Description

A white or almost white, practically odorless, waxy, brittle mass. When heated to 508C it melts to give a colorless or slightly yellowish liquid.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for suppository bases.

Test PhEur 2005 USPNF 23

Identification + —

Characters + —

Melting range 30–458C 27–448C

Residue on ignition — 40.05%

Total ash 40.05% —

Acid value 40.5 41.0

Iodine value 43.0 47.0

Saponification value 210–260 215–255

Hydroxyl value 450 470

Peroxide value 43.0 —

Unsaponifiable matter 40.6% 43.0%

Alkaline impurities + +

Heavy metals 410 ppm —

Typical Properties

Acid value: see Table III.

Color number:

43 for Massa estarinum (iodine color index);

43 for Suppocire excluding L grades (Gardener scale);

45 for Suppocire L grades (Gardener scale);

43 for Witepsol (iodine color index).

Density:

0.955–0.975 g/cm3 for Massa estarinum at 208C; 0.950–0.960 g/cm3 for Suppocire at 208C;

<0.5% w/w for Suppocire;

40.2% w/w for Witepsol.

Peroxide value:

43 for Massa estarinum;

41.2 for Suppocire;

43 for Witepsol.

Saponification value: see Table III.

Solidification point: see Table III.

Solubility: freely soluble in carbon tetrachloride, chloroform, ether, toluene, and xylene; slightly soluble in warm ethanol; practically insoluble in water.

Specific heat:

≈2.6 J/g/8C for Massa estarinum;

1.7–2.5 J/g/8C for Suppocire;

≈2.6 J/g/8C for Witepsol.

Unsaponifiable matter: see Table III.

Stability and Storage Conditions

Hard fat suppository bases are fairly stable toward oxidation and hydrolysis, with the iodine value being a measure of their resistance to oxidation and rancidity. Water content is usually low and deterioration due to hygroscopicity rarely occurs.

Melting characteristics, hardness, and drug-release profiles alter with time, and the melting point may rise by more than 1.08C after storage for several months. Owing to the complex- ity of bases, elucidation of the mechanisms that induce these changes on aging is difficult. Evidence has been presented(3) that supports a finite transition from amorphous to crystalline forms in which polymorphism may or may not contribute, whereas other workers have found melting point changes to be closely associated with the conversion of triglycerides to more stable polymorphic forms.(4) Before melting point determina- tions are made, bases are ‘conditioned’ to a stable crystalline form.

Suppository bases should be stored protected from light in an airtight container at a temperature at least 58C less than their stated melting point. Refrigeration is usually recommended for molded suppositories.

Suppositories that are not effectively packaged may develop a ‘bloom’ of powdery crystals at the surface. This is usually due to the presence of high-melting-point components in the base and can often be overcome by using a different base. Alternatively, the base can be precrystallized prior to pouring, since the crystals will cause a quick and complete crystallization into its end crystal form. This process is called ‘tempering.’

Incompatibilities

Incompatibilities with suppository bases are not now exten- sively reported in the literature. The occurrence of a chemical reaction between a hard fat suppository base and a drug is relatively rare, but any potential for such a reaction may be indicated by the magnitude of the hydroxyl value of the base. The risk of hydrolysis of aspirin, for example, may be reduced

by the use of a base with a low hydroxyl value (<5) and,

764 Suppository Bases, Hard Fat

Table III: Typical properties of suppository bases.

Product Acid value Hydroxyl value Iodine value Melting point (8C) Saponification value Solidification point (8C) Unsaponifiable matter (%)

Cremao CS-34 <0.3 — <2 33–35 250 — —

CS-36 <0.3 — <1 34–37 250 — —

Massa Estarinum B 40.3 20–30 43 33–35.5 225–240 31–33 40.3

BC 40.3 30–40 43 33.5–35.5 225–240 30.5–32.5 40.3

C 40.3 20–30 43 36–38 225–235 33–35 40.3

299 40.3 42 43 33.5–35.5 240–255 32–34.5 40.3

Massupol — — 42 34–36 240–250 31–32.5 — —

Massupol 15 — — 43 35–37 220–230 31–33 — —

Suppocire A <0.5 20–30 <2 35–36.5 225–245 — 40.5

AM <0.2 46 <2 35–36.5 225–245 — 40.5

AML <0.5 46 <2 35–36.5 225–245 — 40.6

AIML <0.5 46 <3 33–35 225–245 — 40.6

AS2 <0.5 15–25 <2 35–36.5 225–245 — 40.5

AS2X <0.5 15–25 <2 35–36.5 225–245 — 40.6

AT <0.5 25–35 <2 35–36.5 225–245 — 40.5

AP <1.0 30–50 <1 33–35 200–220 — 40.5

AI <0.5 20–30 <2 33–35 225–245 — 40.5

AIX <0.5 20–30 <2 33–35 220–240 — <0.6

AIM <0.3 <6 <2 33–35 225–245 — 40.5

AIP <1.0 30–50 <1 30–33 205–225 — <0.5

B <0.5 20–30 <2 36–37.5 225–245 — 40.5

BM <0.2 <6 <2 36–37.5 225–245 — 40.5

BML <0.5 <6 <3 36–37.5 225–245 — 40.6

BS2 <0.5 15–25 <2 36–37.5 225–245 — 40.5

BS2X <0.5 15–25 43 36–37.5 220–240 — 40.6

BT <0.5 25–35 <2 36–37.5 225–245 — 40.5

BP <1.0 30–50 <1 36–37 200–220 — <0.5

C <0.5 20–30 <2 38–40 220–240 — 40.5

CM <0.2 <6 <2 38–40 225–245 — 40.5

CS2 <0.5 15–25 <2 38–40 220–240 — 40.5

CS2X <0.5 15–25 <2 38–40 220–240 — <0.6

CT <0.5 25–35 <2 38–40 220–240 — 40.5

CP <1.0 450 <1 37–39 200–220 — <0.5

D <0.5 20–30 <2 42–45 215–235 — 40.5

DM <0.2 <6 <2 42–45 215–235 — 40.5

NA <0.5 <40 <2 35.5–37.5 225–245 — <0.5

NB <0.5 <40 <2 36.5–38.5 215–235 — <0.5

NC <0.5 <40 <2 38.5–40.5 220–240 — <0.5

NAI 0 <0.5 43 <2 33.5–35.5 220–245 — <0.5

NAI 5 <0.5 45 <2 33.5–35.5 220–245 — <0.5

NAI 10 <0.5 <15 <2 33.5–35.5 220–245 — <0.5

NAI <0.5 <40 <2 33.5–35.5 225–245 — <0.5

NAIL <1.0 <40 <3 33.5–35.5 225–245 — <0.6

NAIX <0.5 <40 <2 33.5–35.5 220–240 — <0.6

NA 0 <0.5 43 <2 35.5–37.5 225–245 — <0.5

NA 5 <0.5 45 <2 35.5–37.5 225–245 — <0.5

NA 10 <0.5 415 <2 35.5–37.5 225–245 — <0.5

NAL <0.5 <40 <2 33.5–35.5 225–245 — <0.6

NAX <0.5 <40 <2 35.5–37.5 220–240 — <0.6

NBL <0.5 <40 <3 36.5–38.5 220–240 — <0.6

NBX <0.5 <40 <2 36.5–38.5 215–235 — <0.6

ND <0.5 <40 <2 42–45 210–230 — <0.5

Witepsol H5 40.2 45 42 34–36 235–245 33–35 40.3

H12 40.2 5–15 43 32–33.5 240–255 29–33 40.3

H15 40.2 5–15 43 33.5–35.5 230–245 32.5–34.5 40.3

H19(a) 40.2 20–30 47 33.5–35.5 230–240 — 40.3

H32 40.2 43 43 31–33 240–250 30–32.5 40.3

H35 40.2 43 43 33.5–35.5 240–250 32–35 40.3

H37 40.2 43 43 36–38 225–245 35–37 40.3

H175(a) 40.7 5–15 43 34.5–36.5 225–245 32–34.5 41.0

H185 40.2 5–15 43 38–39 220–235 34–37 40.3

Continued

Suppository Bases, Hard Fat 765

Table III: Continued

Product Acid

value Hydroxyl value Iodine value Melting point (8C) Saponification value Solidification point (8C) Unsaponifiable matter (%)

Witepsol (cont.) W25 40.3 20–30 43 33.5–35.5 225–240 29–33 40.3

W31 40.3 25–35 43 35–37 225–240 30–33 40.5

W32 40.3 40–50 43 32–33.5 225–245 25–30 40.3

W35 40.3 40–50 43 33.5–35.5 225–235 27–32 40.3

W45 40.3 40–50 43 33.5–35.5 225–235 29–34 40.3

S51(a) 41.0 55–70 48 30–32 215–230 25–27 42.0

S52(a) 41.0 50–65 43 32–33.5 220–230 27–30 42.0

S55(a) 41.0 50–65 43 33.5–35.5 215–230 28–33 42.0

S58(a) 41.0 60–70 47 31.5–33 215–225 27–29 42.0

E75(a) 41.3 5–15 43 37–39 220–230 32–36 43.0

E76 40.3 30–40 43 37–39 220–230 31–35 40.5

E85 40.3 5–15 43 42–44 220–230 37–42 40.5

(a) Note that these types are mixtures containing hard fat and therefore do not comply with the specifications of the PhEur 2005 and USPNF 23.

additionally, by minimization of the water content of both the base and the aspirin.

There is evidence that aminophylline reacts with the glycerides in some hard fat bases to form diamides. On aging or exposure to elevated temperatures, degradation is accom- panied by hardening and suppositories tend to exhibit a marked increase in melting point. The ethylenediamine content is also reduced.(5,6)

Certain fat-soluble medications, such as chloral hydrate, may depress the melting point when incorporated into a base. Similarly, when large amounts of an active substance, either solid or liquid, have to be dispersed into a base, the rheological characteristics of the resultant suppository may be changed, with concomitant effects on release and absorption. Careful selection of bases or the inclusion of additives may therefore be necessary.

Method of Manufacture

The most common method of manufacture involves the hydrolysis of natural vegetable oils such as coconut or palm kernel oil, followed by fractional distillation of the free fatty acids produced. The C8 to C18 fractions are then hydrogenated and reesterified under controlled conditions with glycerin to form a mixture of tri-, di-, and monoglycerides of the required characteristics and hydroxyl value. This process is used for Witepsol.

In an alternative procedure, coconut or palm kernel oil is directly hydrogenated and then subjected to an interesterifica- tion either with itself or with glycerin to form a mixture of tri-, di-, and monoglycerides of the required characteristics and hydroxyl value, e.g. Suppocire.

Safety

Suppository bases are generally regarded as nontoxic and nonirritant materials when used in rectal formulations. How- ever, animal studies have suggested that some bases, particu- larly those types with a high hydroxyl value, may be irritant to the rectal mucosa.(7)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. There is a slight fire hazard on exposure to heat or flame.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (rectal and vaginal preparations). Included in nonparenteral medicines licensed in the UK.

Related Substances

Glycerin; medium-chain triglycerides; polyethylene glycol; theobroma oil.

Theobroma oil

CAS number: [8002-31-1]

Synonyms: cocoa butter; oleum cacao; oleum theobromatis.

Appearance: a yellowish or white, brittle solid with a slight odor of cocoa.

Melting point: 31–348C

Solubility: freely soluble in chloroform, ether, and petroleum spirit; soluble in boiling ethanol; slightly soluble in ethanol (95%).

Stability and storage conditions: heating theobroma oil to more than 368C during the preparation of suppositories can result in an appreciable lowering of the solidification point owing to the formation of metastable states; this may lead to difficulties in the setting of the suppository. Theobroma oil should be stored at a temperature not exceeding 258C.

Comments: theobroma oil is a fat of natural origin used as a suppository base. It comprises a mixture of the triglycerides of saturated and unsaturated fatty acids, in which the unsaturated acid is preferentially situated on the 2-position of the glyceride. Theobroma oil is also a major ingredient of chocolate.

Comments

—

766 Suppository Bases, Hard Fat

Specific References

Setnikar I, Fantelli S. Softening and liquefaction temperature of suppositories. J Pharm Sci 1963; 52: 38–43.

Kro´ wczynski L. A simple device for testing suppositories [in Polish]. Diss Pharm 1959; 11: 269–273.

Coben LJ, Lordi NG. Physical stability of semisynthetic supposi- tory bases. J Pharm Sci 1980; 69: 955–960.

Liversidge GG, Grant DJW, Padfield JM. Influence of physico- chemical interactions on the properties of suppositories I: interactions between the constituents of fatty suppository bases. Int J Pharm 1981; 7: 211–223.

Brower JF, Juenge EC, Page DP, Dow ML. Decomposition of aminophylline in suppository formulations. J Pharm Sci 1980; 69: 942–945.

Taylor JB, Simpkins DE. Aminophylline suppositories: in vitro dissolution and bioavailability in man. Pharm J 1981; 227: 601– 603.

De Muynck C, Cuvelier C, Van Steenkiste D, et al. Rectal mucosa damage in rabbits after subchronical application of suppository bases. Pharm Res 1991; 8: 945–950.

General References

Allen LV. Compounding suppositories Part I: Theoretical considera- tions. Int J Pharm Compound 2000; 4(4): 289–293: 324–325.

Allen LV. Compounding suppositories Part II: Extemporaneous preparation. Int J Pharm Compound 2000; 4(5): 372–373, 404–

405.

Anschel J, Lieberman HA. Suppositories. In: Lachman L, Lieberman HA, Kanig JL, eds. The Theory and Practice of Industrial Pharmacy, 2nd edn. Philadelphia: Lea and Febiger, 1976: 245–269.

Realdon N, Ragazzi E, Dal-Zotto M. Effects of silicon dioxide on drug release from suppositories. Drug Dev Ind Pharm 1997; 23(11): 1025–1041.

Realdon N, Ragazzi E, Dal-Zotto M. Layered excipient suppositories: the possibility of modulating drug availability. Int J Pharm 1997; 148: 155–163.

Schoonen AJM, Moolenarr F, Huizinga T. Release of drugs from fatty suppository bases I: the release mechanism. Int J Pharm 1979; 4: 141–152.

Senior N. Review of rectal suppositories 1: formulation and manu- facture. Pharm J 1969; 203: 703–706.

Senior N. Review of rectal suppositories 2: resorption studies and medical applications. Pharm J 1969; 203: 732–736.

Senior N. Rectal administration of drugs. In: Bean HS, Beckett AH, Carless JE, eds. Advances in Pharmaceutical Sciences, vol. 4. London: Academic Press, 1974: 363–435.

Sutananta W, Craig DQM, Newton JM. An evaluation of the mechanism of drug release from glyceride bases. J Pharm Pharma- col 1995; 47: 182–187.

BP: Purified talc JP: Talc

PhEur: Talcum USP: Talc

Synonyms

Altalc; E553b; hydrous magnesium calcium silicate; hydrous magnesium silicate; Luzenac Pharma; magnesium hydrogen metasilicate; Magsil Osmanthus; Magsil Star; powdered talc; purified French chalk; Purtalc; soapstone; steatite; Superiore.

Chemical Name and CAS Registry Number

Talc [14807-96-6]

Empirical Formula and Molecular Weight

Talc is a purified, hydrated, magnesium silicate, approximating to the formula Mg6(Si2O5)4(OH)4. It may contain small, variable amounts of aluminum silicate and iron.

Structural Formula

See Section 4.

Functional Category

Anticaking agent; glidant; tablet and capsule diluent; tablet and capsule lubricant.

Applications in Pharmaceutical Formulation or Technology

Talc was once widely used in oral solid dosage formulations as a lubricant and diluent, see Table I,(1–3) although today it is less commonly used. However, it is widely used as a dissolution retardant in the development of controlled-release pro- ducts.(4–6) Talc is also used as a lubricant in tablet formula- tions;(7) in a novel powder coating for extended-release pellets;(8) and as an adsorbant.(9)

In topical preparations, talc is used as a dusting powder, although it should not be used to dust surgical gloves; see Section 14. Talc is a natural material; it may therefore frequently contain microorganisms and should be sterilized when used as a dusting powder; see Section 11.

Talc is additionally used to clarify liquids and is also used in cosmetics and food products, mainly for its lubricant proper- ties.

Table I: Uses of talc.

Use Concentration (%)

Dusting powder 90.0–99.0

Glidant and tablet lubricant 1.0–10.0

Tablet and capsule diluent 5.0–30.0

Description

Talc is a very fine, white to grayish-white, odorless, impalpable, unctuous, crystalline powder. It adheres readily to the skin and is soft to the touch and free from grittiness.

SEM: 1

Excipient: Talc (Purtalc)

Manufacturer: Charles B Chrystal Co., Inc.

Lot No.: 1102A-2

Magnification: 1200×

Voltage: 10 kV

Pharmacopeial Specifications

See Table II.

Typical Properties

Acidity/alkalinity: pH = 7–10 for a 20% w/v aqueous dispersion.

Hardness (Mohs): 1.0–1.5

Moisture content: talc absorbs insignificant amounts of water at 258C and relative humidities up to about 90%.

Particle size distribution: varies with the source and grade of material. Two typical grades are 599% through a 74 mm (#200 mesh) or 599% through a 44 mm (#325 mesh).

Refractive index: n20 = 1.54–1.59

Solubility: practically insoluble in dilute acids and alkalis, organic solvents, and water.

Specific gravity: 2.7–2.8

Specific surface area: 2.41–2.42 m2/g

768 Talc

Table II: Pharmacopeial specifications for talc.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Characters + + —

Acid-soluble substances 42.0% — 42.0%

Acidity or alkalinity — + —

Production — + —

pH — 7.0–9.0 —

Water-soluble substances — 40.2% 40.1%

Magnesium — 17.0–19.5 —

Loss on ignition 45.0% 47.0% 46.5%

Microbial contamination — + 4500/g

Aerobic bacteria — 4102/g —

Fungi — 4102/g —

Acid and alkali-soluble 44.0 mg — 42.0%

substances

Water-soluble iron + — +

Arsenic 44 ppm — 43 ppm

Heavy metals — — 40.004%

Lead — — 40.001%

Stability and Storage Conditions

Talc is a stable material and may be sterilized by heating at 1608C for not less than 1 hour. It may also be sterilized by exposure to ethylene oxide or gamma irradiation.(10)

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

Incompatibilities

Incompatible with quaternary ammonium compounds.

Method of Manufacture

Talc is a naturally occurring hydropolysilicate mineral found in many parts of the world including Australia, China, Italy, India, France, and the USA.(11)

The purity of talc varies depending on the country of origin. For example, Italian types are reported to contain calcium silicate as the contaminant; Indian types contain aluminum and iron oxides; French types contain aluminum oxide; and American types contain calcium carbonate (California), iron oxide (Montana), aluminum and iron oxides (North Carolina), or aluminum oxide (Alabama).(12)

Naturally occurring talc is mined and pulverized before being subjected to flotation processes to remove various impurities such as asbestos (tremolite); carbon; dolomite; iron oxide; and various other magnesium and carbonate minerals. Following this process, the talc is finely powdered, treated with dilute hydrochloric acid, washed with water, and then dried. The processing variables of agglomerated talc strongly influ- ence its physical characteristics.(13–15)

Safety

Talc is used mainly in tablet and capsule formulations. Talc is not absorbed systemically following oral ingestion and is therefore regarded as an essentially nontoxic material. How-

ever, intranasal or intravenous abuse of products containing talc can cause granulomas in body tissues, particularly the lungs.(16–18) Contamination of wounds or body cavities with talc may also cause granulomas; therefore, it should not be used to dust surgical gloves. Inhalation of talc causes irritation and may cause severe respiratory distress in infants;(19) see also Section 15.

Although talc has been extensively investigated for its carcinogenic potential, and it has been suggested that there is an increased risk of ovarian cancer in women using talc, the evidence is inconclusive.(20,21) However, talc contaminated with asbestos has been proved to be carcinogenic in humans, and asbestos-free grades should therefore be used in pharma- ceutical products.(22)

Also, long-term toxic effects of talc contaminated with large quantities of hexachlorophene caused serious irreversible neurotoxicity in infants accidentally exposed to the sub- stance.(23)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Talc is irritant if inhaled and prolonged excessive exposure may cause pneumoconiosis.

In the UK, the occupational exposure limit for talc is 1 mg/m3 of respirable dust long-term (8-hour TWA).(24) Eye protection, gloves, and a respirator are recommended.

Regulatory Status

Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (buccal tablets; oral capsules and tablets; rectal and topical preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Bentonite; magnesium aluminum silicate; magnesium silicate; magnesium trisilicate.

Comments

Various different grades of talc are commercially available that vary in their chemical composition depending upon their source and method of preparation.(11,25,26)

Talc derived from deposits that are known to contain associated asbestos is not suitable for pharmaceutical use. Tests for amphiboles and serpentines should be carried out to ensure that the product is free of asbestos. A specification for talc is contained in the Food Chemicals Codex (FCC).

The EINECS number for talc is 238-877-9.

Specific References

Dawoodbhai S, Rhodes CT. Pharmaceutical and cosmetic uses of talc. Drug Dev Ind Pharm 1990; 16: 2409–2429.

Dawoodbhai S, Suryanarayan ER, Woodruff CW. Optimization of tablet formulations containing talc. Drug Dev Ind Pharm 1991; 17: 1343–1371.

Wang DP, Yang MC, Wong CY. Formulation development of oral controlled release pellets of diclofenac sodium. Drug Dev Ind Pharm 1997; 23: 1013–1017.

Fassihi RA, McPhillips AM, Uraizee SA, Sakr AM. Potential use of magnesium stearate and talc as dissolution retardants in the development of controlled release drug delivery systems. Pharm Ind 1994; 56: 579–583.

Talc 769

Fassihi R, Fabian J, Sakr AM. Application of response surface methodology to design optimization in formulation of a typical controlled release system. Drugs Made Ger 1996; 39(Oct–Dec): 122–126.

Schultz P, Tho I, Kleinebudde P. New multiparticulate delayed release system. Part 2. Coating formulation and properties of free films. J Control Release 1997; 47: 191–199.

Oetari RA, Yuwano T, Fudhdi A. Formulation of PGV-O a new antiinflammatory agent as a tablet dosage form. Indonesian J Pharm 2003; 14(4): 160–168.

Pearnchob N, Bodmeier R. Dry powder coating of pellets with micronized Eudragil (R) RS for extended drug release. Pharm Res 2003; 20(12); 1970–1976.

Mani N, Suh HR, Jun HW. Microencapsulation of a hydrophilic drug into a hydrophobic matrix using a salting-out procedure: II. Effects of adsorbents on microsphere properties. Drug Dev Ind Pharm 2004; 30(1): 83–93.

Bubik JS. Preparation of sterile talc for treatment of pleural effusion [letter]. Am J Hosp Pharm 1992; 49: 562–563.

Grexa RW, Parmentier CJ. Cosmetic talc properties and specifica- tions. Cosmet Toilet 1979; 94(2): 29–33.

Hoepfner EM, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas, 5th edn, vol. II. Aulendorf: Editio Cantor Verlag, 2002: 1556–1559.

Lin K, Peck GE. Development of agglomerated talc. Part 1. Evaluation of fluidized bed granulation parameters on the physical properties of agglomerated talc. Drug Dev Ind Pharm 1995; 21: 447–460.

Lin K, Peck GE. Development of agglomerated talc. Part 2. Optimization of the processing parameters for the preparation of granulated talc. Drug Dev Ind Pharm 1995; 21: 159–173.

Lin K, Peck GE. Development of agglomerated talc. Part 3. Comparisons of the physical properties of the agglomerated talc prepared by three different processing methods. Drug Dev Ind Pharm 1996; 22: 383–392.

Schwartz IS, Bosken C. Pulmonary vascular talc granulomatosis.

J Am Med Assoc 1986; 256: 2584.

Johnson DC, Petru A, Azimi PH. Foreign body pulmonary granulomas in an abuser of nasally inhaled drugs. Pediatrics 1991; 88: 159–161.

Sparrow SA, Hallam LA. Talc granulomas [letter]. Br Med J 1991;

303: 58.

Pairaudeau PW, Wilson RG, Hall MA, Milne M. Inhalation of baby powder: an unappreciated hazard. Br Med J 1991; 302: 1200–1201.

Longo DL, Young RC. Cosmetic talc and ovarian cancer. Lancet

1979; ii: 349–351.

Phillipson IM. Talc quality [letter]. Lancet 1980; i: 48.

International Agency for Research on Cancer/World Health Organization. Silica and Some Silicates: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: WHO, 1987: 42.

Anonymous. Long-term sequelae of hexachlorophene poisoning.

Prescrire Int 1992; 1: 168.

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

Phadke DS, Keeney MP, Norris DA. Evaluation of batch-to-batch and manufacturer-to-manufacturer variability in the physical properties of talc and stearic acid. Drug Dev Ind Pharm 1994; 20: 859–871.

Lin K, Peck GE. Characterization of talc samples from different sources. Drug Dev Ind Pharm 1994; 20: 2993–3003.

General References

Gold G, Campbell JA. Effects of selected USP talcs on acetylsalicylic acid stability in tablets. J Pharm Sci 1964; 53: 52–54.

BP: Tartaric acid JP: Tartaric acid

PhEur: Acidum tartaricum USPNF: Tartaric acid

Synonyms

L-(+)-2,3-Dihydroxybutanedioic acid; (2R,3R)-2,3-dihydroxy- butane-1,4-dioic acid; 2,3-dihydroxysuccinic acid; E334; d- tartaric acid; L-(+)-tartaric acid.

Chemical Name and CAS Registry Number

[R-(R*,R*)]-2,3-Dihydroxybutanedioic acid [87-69-4]

Empirical Formula and Molecular Weight

C4H6O6 150.09

Structural Formula

Functional Category

Acidifying agent; flavor enhancer; sequestering agent.

Applications in Pharmaceutical Formulation or Technology

Tartaric acid is used in beverages, confectionery, food products, and pharmaceutical formulations as an acidulant. It may also be used as a sequestering agent and as an antioxidant synergist. In pharmaceutical formulations, it is widely used in combina- tion with bicarbonates, as the acid component of effervescent granules, powders, and tablets.

Description

Tartaric acid occurs as colorless monoclinic crystals, or a white or almost white crystalline powder. It is odorless, with an extremely tart taste.

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