SAS 6 Commercial Manufacturing (Suppositories) Flashcards by Ainah Ramirez

a medicated solid dosage form generally intended for use in the rectum, vagina, and
to a lesser extent, the urethra

suppository

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usually employ vehicles that melt or soften
at body temperature

Rectal and urethral
suppositories

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also made as compressed
tablets that disintegrate in the body fluids

vaginal suppositories/pessaries

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Bruno Solomon published a critical study of
suppository bases, in which he classified them into three
broad types:

(1) cocoa butter

(2) fat and wax combinations with cocoa butter

(3) glycerinated gelatin bases

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In children, this route is especially useful. An ill child may refuse oral medication and may fear injections.

rectal

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Avoids first-pass effect

rectal administration

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Provides better drug stability for drugs susceptible to gastric degradation

rectal administration

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Can administer large doses of drugs compared to oral dosage forms

rectal administration

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Can administer large doses of drugs compared to oral dosage forms

rectal administration

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Can administer large doses of drugs compared to oral dosage forms

rectal administration

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suppository after insertion can leave the anorectal site and ascend to the
rectosigmoid and descending colon. Hence, one may consider that suppositories with this
shape possibly should not be used at bedtime

The ―bullet-shaped‖ suppository

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may interrupt the absorption process of the rectal administrated drug; this may especially occur if the
drug is irritating

Defecation

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intended for local action are most frequently used to relieve constipation or
the pain, irritation, itching, and inflammation associated with hemorrhoids or other anorectal
conditions.

Rectal suppositories

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commonly used to promote laxation by local irritation of
the mucous membranes, probably by the dehydrating effect of the glycerin on
those membranes.

Glycerin suppository

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commonly used as contraceptives, antiseptics in feminine hygiene and
agents to combat specific invading pathogen

Vaginal suppositories

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commonly used as antibacterial or local anesthetic preparative for
local examination.

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For systemic effects, the ________________ of the rectum and vagina permit the absorption of
many soluble drugs

mucous membranes

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m is used frequently as the site for the systemic absorption of drugs, the vagina is not as frequently used for this purpose

rectum

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for the relief of nausea and vomiting and as a
tranquilizer

Prochlorperazine and chlorpromazine

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for opioid analgesia

Morphine and oxymorphone

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for the relief of migraine syndrome

Indomethacin

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a nonsteroidal anti-inflammatory analgesic and antipyretic

Indomethacin

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for the relief of nausea and vomiting

Ondansetron

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is usually determined by the USP method,
manufacturers of bases occasionally use different methods for determining melting
characteristics, such as ―Wiley melting point,‖ ―capillary melting point,‖ ―softening
point,‖ ―incipient melting (or thaw) point,‖ and others

melting range‖

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either entirely natural or synthetic, or modified natural products

source of origin

compound, or a well-defined or poorly elucidated mixture

chemical makeup

is a measure of the percentage of fat in crystalline (solid) phase to total fat (the remainder being in liquid phase) across a temperature gradient.

Solid fat index (SFI)

This method is based on measuring the heat of fusion successively at different temperatures.

Solid-fat index (SFI)

By reference to the total melting heat, the fraction of fat melted is determined

Solid-fat index (SFI)

This technique is faster than dilatometry, and gives results comparable with NMR.

Solid-fat index (SFI)

This is a measure of unesterified positions on glyceride molecules and reflects the monoglyceride and diglyceride content of a fatty base.

Hydroxyl Value

This value allows prediction of the time required for solidifying the base when it is chilled in the mold.

Solidification point

The number represents the milligrams of KOH that would neutralize the acetic acid used to acetylate 1 g of fat.

Hydroxyl Value

If the interval between the melting range and solidification point is 10°C or more, the time required for solidification may have to be shortened by augmenting refrigeration to produce a more efficient manufacturing procedure.

Solidification point

The number of milligrams of potassium hydroxide required to neutralize the free acids and saponify the esters contained in 1 g of a fat is an indication of the type (mono-, di-, or tri-) glyceride, as well as the amount of glyceride present.

Saponification Value

This value expresses the number of grams of iodine that reacts with 100 g of fat or other unsaturated material.

Iodine Value

The possibility of decomposition by moisture, acids, and oxygen (which leads to rancidity in fats) increases with high iodine values.

Iodine Value

The amount of water, in grams, that can be incorporated in 100 g of fat is expressed by this value.

Water Number

can be increased by the addition of surface active agents, monoglycerides, and other emulsifiers

Water number

The number of milligrams of potassium hydroxide required to neutralize the free acid in 1 g of substance is expressed by this value.

Acid value

complete absence of acid is important for good suppository bases.

Low ―acid values

complicate formulation work, because they react with other ingredients and can also cause irritation when in contact with mucous membranes.

Free acids

The ―acid value‖ is

below 0.2

The ―saponification value‖

ranges from 200 to 245

The ―iodine value‖ is

less than 7

The ―iodine value‖ is

small or the SFI curve is sharp

Most frequently employed suppository base

Fatty or Oleaginous Bases

Most common base used for rectal suppositories

Cocoa butter, NF

Most common base used for rectal suppositories, spreading action.

Cocoa butter, NF

Fat obtained from the roasted seed of Theobroma cacao

Cocoa butter, NF

At room temperature, it is a yellowish-white solid having a faint, agreeable chocolate-like odor.

Cocoa butter, NF

It melts at 30°C to 36°C (86°F to 97°F), making it an ideal suppository base, melting just below body temperature and yet maintaining its solidity at usual room temperatures.

Cocoa butter, NF

least stable cocoa butter

Alpha (α)

most stable cocoa butter , solid until 32°C and melts at around 34-35°C

Beta (β)

can decrease Beta cocoa butter melting point when incorporated w/ it

Phenol & Chloral Hydrate

Made from triglycerides from palm, palm kernel, and coconut oils with self-emulsifying glyceryl monostearate and polyoxyl stearate

Fattibase

From triglycerides derived from coconut oil

From triglycerides of saturated fatty acids C12–C18 with varied portions of the corresponding partial glycerides

Witepsol

Witepsol, Major:

Lauric acid

The main members of this group are glycerinated gelatin and polyethylene glycols

Water-soluble and Water-miscible Bases

During administration, moisten the tip of the suppository to prevent mucosal irritation and to facilitate the smooth passage of suppository in the body-orifices.

Water-soluble and Water-miscible Bases

Most frequently used in preparation of vaginal suppositories

Glycerinated gelatin

Slower to soften and mix w/ the physiologic fluids

Glycerinated gelatin

Polymers of ethylene oxide and water

Polyethylene glycols

Do not melt at body temperature but rather dissolve slowly in the body’s fluid

Polyethylene glycols

Commonly employed for vaginal administration

Polyethylene glycols

These are mixtures of oleaginous and water-soluble or water-miscible materials

Miscellaneous Bases

a surface-active agent that is employed in a number of commercial suppository base

Polyoxyl 40 stearate

Generally combination of lipophilic and hydrophilic substances

Miscellaneous Bases

The simplest and oldest method of preparing a suppository is by hand, i.e., by rolling the well-blended suppository base containing the active ingredients into the desired shape.

Hand Molding

This method is practical and economical for the manufacture of small numbers of suppositories.

Hand Molding

is simple and results in a more elegant appearance than does hand molding. It avoids the possibilities of sedimentation of the insoluble solids in the suppository base, but is too slow for large-scale production.

cold compression method

A more uniform and pharmaceutically elegant suppository can be made by compressing the cold-grated mass into a desired shape.

Compression Molding

One of the major disadvantages of the use of the cold compression technique for molding fat-type base suppositories is

air entrapment

This unavoidable inclusion of air makes close weight control impossible and also favors the possible oxidation of both the base and active ingredients

air entrapment

The most commonly used method for producing suppositories on both a small and a large scale is the molding process.

Pour Molding

A significant advance in suppository manufacturing was the development of automated methods for molding suppositories directly in their wrapping material. This is currently accomplished with either plastic or aluminum foil.

In-package Molding

Machines utilizing plastic either thermoform the mold and fill the mold in sequence, or simply fill the mass into previously thermoformed molds. Machines using aluminum foil/ polypropylene/lacquer laminates emboss two parallel strips of foil so that when they are sealed together, molds are formed.

In-package Molding

accelerates the oxidation of fats

Water

Glycerinated gelatin suppositories lose moisture by evaporation in dry climates and absorb moisture under conditions of high humidity.

Hygroscopicity

The rate of moisture change in polyethylene glycol bases depends not only on humidity and temperature, but also on the chain length of the molecule.

Hygroscopicity

is important in the manufacture of the suppository and to its behavior in the rectum after melting.

Viscosity

Suppositories made from cocoa butter are quite elastic and do not fracture readily. Synthetic fat bases with a high degree of hydrogenation and high stearate contents, and therefore a higher solids content at room temperature, are usually more brittle.

Brittleness

To calculate the amount of drug per suppository, the ___________ of the base must be known.

denisty

This phenomenon occurs in many melted suppository bases after cooling in the mold.

Volume Contraction

This is caused by the mass pulling away from the sides of the mold. This contraction facilitates the removal of the suppositories from the mold, eliminating the need for mold release agents.

Good mold release

This undesirable feature results in lowered suppository weight and imperfect appearance of the suppository.

Contraction hole formation at the open end of the mold

Mineral oil, an aqueous solution of sodium lauryl sulfate, various silicones, alcohol, and tincture of green soap are examples of agents employed for this purpose. They are applied by wiping, brushing, or spraying.

Lubricants or Mold Release Agents

Cocoa butter adheres to suppository molds because of its low volume contraction. These suppositories are difficult to remove from the molds, and various mold lubricants or release agents must be used to overcome this difficulty.

Lubricants or Mold Release Agents

results from the autoxidation and subsequent decomposition of unsaturated fats into low- and medium-molecular-weight saturated and unsaturated aldehydes, ketones, and acids, which have strong, unpleasant odors.

Rancidity

This test is also called the macromelting range test and is a measure of the time it takes for the entire suppository to melt when immersed in a constant-temperature (37°C) water bath. In contrast, the micromelting range test is the melting range measured in capillary' tubes for the fat base only.

Melting Range Test

A modification of a method developed by Krowczynski is another useful test of finished suppositories.

Liquefaction or Softening Time Tests

It consists of a U-tube partially submersed in a constant-temperature water bath. A constriction on one side holds the suppository in place in the tube.

Liquefaction or Softening Time Tests

measures the liquefaction time of rectal suppositories in an apparatus that simulates in vivo condition.

softening time

A glass rod is placed on top of the suppository, and the time for the rod to pass through to the constriction is recorded as the

softening time

designed as a method for measuring the fragility or brittleness of suppositories. The apparatus used for the test consists of a double-wall chamber in which the test suppository is placed.

breaking test

The test is conducted by placing 600 g on the platform. At 1 -min intervals, 200-g weights are added, and the weight at which the suppository collapses is the breaking point, or the force that determines the fragility or brittleness characteristics of the suppository.

Breaking Test

Testing for the rate of in vitro release of drug substances from suppositories has always posed a difficult problem, owing to melting, deformation, and dispersion in the dissolution medium.

Dissolution Testing

Early testing was carried out by simple placement in a beaker containing a medium

Dissolution Testing