UCPharmacy-Drug Formulation Science

Learning Resources

TOPIC ONE: Powders and granules

The word "powder" refers to a chemical or mixture that is solid in physical state. In compounding, "powder" refers to a dosage formulation that is solid in physical state. But the formulation may be composed of only the active drug or may be a mixture of the active drug and other ingredients.

Powders offer some unique advantages:

each dose can contain a different amount of active drug
can be administered easily to infants and young children who cannot swallow tablets or capsules
drug will have a rapid onset of action since disintegration is not required
can be applied to many body cavities such as ears, nose, tooth socket, throat
drugs tend to most stable as a solid
can be made into many different dosage formulations (capsules, tablets, powders for reconstitution, dusting powders, bulk powders, powders for inhalation, etc.)

Pharmaceutical powders are formulated to be exist as fine particles. The powders are then smooth to the touch and nonirritating to the skin. Powders generally range from 0.1 to 10 micron in size. The size of the particles are often expressed as a number which corresponds to the mesh screen size of a sieve.

The USP 24/NF19 uses descriptive terms to define powder fineness. The table below shows the correlation their classification.

Description Term	Mesh Opening Size (microns)	Mesh Size Number
Very Coarse	> 1000	2 - 10
Coarse	355 -1000	20 - 40
Moderately Coarse	180 - 355	40 - 80
Fine	125 - 180	80 - 120
Very Fine	90 - 125	120 - 200

A good powder formulation has an uniform particle size distribution. If the particle size distribution is not uniform, the powder can segregate according to the different particle sizes which may result in inaccurate dosing or inconsistent performance. A uniform particle size distribution insures an uniform dissolution rate if the powder is to dissolve, an uniform sedimentation rate if the powder is used in a suspension, and minimizes stratification when powders are stored or transported.

Reducing the particle size of a powder will result in an uniform distribution of particle sizes. The process of reducing the particle size is called comminution. In extemporaneous compounding, there are three methods of comminution:

Trituration is the continuous rubbing or grinding of the powder in a mortar with a pestle. This method is used when working with hard, fracturable powders.

Pulverization by Intervention is used with hard crystalline powders that do not crush or triturate easily, or gummy-type substances. The first step is to use an "intervening" solvent (such as alcohol or acetone) that will dissolve the compound. The dissolved powder is then mixed in a mortar or spread on an ointment slab to enhance the evaporation of the solvent. As the solvent evaporates, the powder will recrystallize out of solution as fine particles.
Levigation reduces the particle size by triturating it in a mortar or spatulating it on an ointment slab or pad with a small amount of a liquid in which the solid is not soluble. The solvent should be somewhat viscous such as mineral oil or glycerin. This method is also used to reduce the particle size of insoluble materials when compounding ointments and suspensions.

Classification of Powders

Bulk Powders

Bulk powders are nonpotent and can be dosed with acceptable accuracy and safety using measuring devices such as the teaspoon, cup, or insufflator. This practically limits the use of orally administered bulk powders to antacids, dietary supplements, laxatives, and a few analgesics. Many bulk powders are used topically.

Dusting Powders

Dusting powders are fine medicinal (bulk) powders intended to be dusted on the skin by means of sifter-top containers. A single medicinal agent may be used as a dusting powder; however, a base is frequently used to apply a medicinal agent and to protect the skin from irritation and friction. Bentonite, kaolin, kieselguhr, magnesium carbonate, starch, and talc are used as inert bases for dusting powders. Powder bases absorb secretions and exert a drying effect, which relieves congestion and imparts a cooling sensation. All extemporaneous dusting powders should be passed through a 100-200 mesh sieve to ensure that they are grit free and will not further mechanically irritate traumatized areas.

Douche Powders

Douche powders are used to prepare solutions that cleanse the vagina. Most douche powders are used for their hygienic effects, but a few contain antibiotics.

Douche powders are prescribed as a matter of convenience for the patient, since a powder is more portable than a bulky solution. The formula is developed so that a teaspoonful or tablespoonful of powder dissolved in a specified volume of water provides the desired concentration. The pH usually ranges from 3.5 to 5 when the solution is prepared. Feminine bulb syringes or fountain syringes are used for vaginal irrigation. Since many of the ingredients are volatile (e.g., menthol, thymol, and volatile oils), douche powders should be packaged in glass jars with a wide mouth. Some commercial douche powders are available in metal foil packets, which contain the proper amount of powder for a single douche. Many douches are also available as prepared unit of use solutions in disposable applicators.

Insufflations

Insufflations are extremely fine powders to be introduced into body cavities. To administer an insufflation, the powder is placed in the insufflator, and when the bulb is squeezed, the air current carries the fine particles through the nozzle to the region for which the medication is intended. All extemporaneously compounded insufflations must be passed through a 100 mesh sieve. Pressurized packages provide an elegant approach to the administration of insufflations.

Powder Sprays

In contrast to dusting powders, powders dispensed under pressure will deliver targeted and uniform application at the desired site. Also, in an aerosol container medicated powders may be maintained in a sterile condition. The powder particles must be a definite size range to prevent clogging of the valve orifice and to provide uniformity of application. In general, powders that are to be packaged as powder sprays must not contain particles greater than 50 microns if they are to be sprayed successfully.

Divided Powders (Chartulae; Charts; Powder Papers)

Divided powders or charts are single doses of powdered medicinals individually wrapped in cellophane, metallic foil, or paper. The divided powder is a more accurate dosage form than bulk powder because the patient is not involved in measurement of the dose. Cellophane and foil-enclosed powders are better protected from the external environment until the time of administration than paper-enclosed powders.Divided powders are commercially available in foil, cellophane or paper packs.

Granulations

Granules are particles ranging in size from about 4 to 10 mesh. Granules generally are made by first blending the powders together and then moistening the mixture to form a pasty mass. The mass is passed through a sieve and then dried in air or in an oven. They are prepared as a convenience for packaging, as a more stable product due to less surface exposure, and as a popular dosage form. Granulations are also used as intermediates in the preparation of capsules and tablets, since they flow more smoothly and predictably than do small powder particles.

The most popular compounded granulation is the effervescent powder (sometimes called effervescent salts). These granulations are popular due to their taste and psychological impression. When added to water, the granulation effervesces ("fizzes") as carbon dioxide is liberated.

Preparation of Effervescent Granulation

It has been found that citric acid monohydrate and tartaric acid used in the ratio of 1:2, respectively, produces a powder with good effervescent properties. Citric acid monohydrate is not used alone because it results in a sticky mixture that will not easily granulate. Tartaric acid is not used alone because the granules are too friable and crumble. The amount of sodium bicarbonate to be used may be calculated from the reaction which occur when the granules come in contact with water.

Useful video resources

Effervescent Powders

How to fold powder papers (divided powders)

TOPIC TWO: Tablets

ntroduction Without question, the compressed tablet is one of the most popular dosage forms today. About one-half of all prescriptions dispensed are for tablets. Usually one considers a compressed tablet as an oral medication; however, tablets have many other uses. The sublingual tablet, the pellet, the wafer, the troche, and the vaginal insert are manufactured by the same procedure as an oral tablet.

There are three methods of commercially making compressed tablets:

The direct compression method A compressible vehicle is blended with the medicinal agent, and if necessary, with a lubricant and a disintegrant, and then the blend is compressed. Substances that are commonly used as directly compressible vehicles are: anhydrous lactose, dicalcium phosphate (Emcompress), granulated mannitol, microcrystalline cellulose (Avicel), compressible sugar (Di-Pac), starch (Sta-Rx 1500), hydrolyzed starch (Celutab), and a blend of sugar, invert sugar, starch and magnesium stearate (Nutab).

The dry granulation method (slugging method) The ingredients in the formulation are intimately mixed and precompressed on heavy duty tablet machines. The slug which is formed is ground to a uniform size and compressed into the finished tablet.

The wet granulation method This method has more operational manipulations, and is more time-consuming than the other methods. The wet granulation method is not suitable for drugs which are thermolabile or hydrolyzable by the presence of water in the liquid binder. The general steps involved in a wet granulation process are:

The powdered ingredients are weighed and mixed intimately by geometric dilution.
The granulating solution or binder is prepared.
The powders and the granulation solution are kneaded to proper consistency.
The wet mass is forced through a screen or wet granulator.
The granules are dried in an oven or a fluidized bed dryer.
The dried granules are screened to a suitable size for compression.
A lubricant and a disintegrating agent are mixed with the granulation.
The granulation is compressed into the finished tablet.

Useful video resources

The tablet press- watch the video here

How drugs are absorbed (oral route of administration)-watch the video here

Fundamentals of Absorption-watch the video here

Ionization and absorption-watch the video here Drug metabolism-watch the video here

Evaluation of Tablets

Tablets are evaluated by a variety of methods.

Analytical determination of tablet content: This probably will not be done due to the requirement of specialized equipment. However, the weight variation of the tablets can be measured by weighing each individual tablets and determining the percent difference from the intended amount. Guidelines in the USP 24/NF19 Supplement 1 indicate that each tablet "shall be not less than 90% and not more than 110% of the theoretically calculated weight for each unit."

Tablet hardness: The tablets must be hard enough to withstand mechanical stress during packaging, shipment, and handling by the consumer. Section <1216> of the USP 24/NF19 outlines a standard tablet friability test applicable to manufactured tablets. Most compounding pharmacy would not have the apparatus specified in Section <1216>. However, there are several hand operated tablet hardness testers that might be useful. Examples of devices are the Strong Cobb, Pfizer, and Stokes hardness testers. The principle of measurement involves subjecting the tablet to an increasing load until the tablet breaks or fractures. The load is applied along the radial axis of the tablet. Oral tablets normally have a hardness of 4 to 8 or 10 kg; however, hypodermic and chewable tablets are much softer (3 kg) and some sustained release tablets are much harder (10-20 kg).

Tablet disintegration: There are commercially available disintegration and dissolution apparatus. Most pharmacists will not have this equipment. However, a simple disintegration apparatus can be made. Start by supporting a 10 mesh screen about 2 inches above the bottom of a 1000 ml beaker. Fill the beaker with 1000 ml of water, add a stirring bar, and place the beaker on a magnetic stirring plate. Stir at a moderate speed. Drop the tablets onto the mesh screen and record the time needed for the tablets to disintegrate. A reasonable disintegration time should be between 15 and 30 minutes, although the time will depend on the product, the stirring speed, etc.

Tablet dissolution: Disintegration time determination is a useful tool for production control, but disintegration of a tablet does not imply that the drug has dissolved. A tablet can have a rapid disintegration time yet be biologically unavailable. The dissolution rate of the drug from the primary particles of the tablet is the important factor in drug absorption and for many formulations is the rate-limiting step. Therefore, a dissolution time is more indicative of the availability of a drug from a tablet than the disintegration test. Even though this is an important parameter to measure, most pharmacies do not have the equipment needed to conduct these kinds of tests.

TOPIC THREE CAPSULES

Introduction Capsules are gelatin shells filled with the ingredients that make up an individual dose. Dry powders, semi-solids, and liquids that do not dissolve gelatin may be encapsulated. Capsules account for about 20% of all prescriptions dispensed.

Capsules have several advantages as pharmaceutical dosage forms:

They may be used to mask the unpleasant tastes, aromas, or appearance of a drug.
They allow powders to be dispensed in an uncompressed form, thus allowing for quicker dissolution and absorption of the drug following oral dosing (as compared with tablets).
They offer the pharmacist versitility to prepare any dose desired for a variety of administration routes (e.g. oral, inhalation, rectal, or to be diluted for vaginal, rectal, oral, or topical use).
They may be easier than tablets for some people to swallow.
They can be make to alter the release rate of the drug.

Their disadvantages or limitations include the following:

They are easily tampered with (although techniques exist for preventing this).
They are subject to the effects of relative humidity and to microbial contamination.
They may be difficult for some people to swallow.
More expensive (commercially).

Hard Gelatin Capsules Relative Size of CapsulesThe hard gelatin capsule consists of a base or body and a shorter cap, which fits firmly over the base of the capsule. For human use, eight sizes of capsules are available. The capacity of each size varies according to the combination of drugs and their apparent densities. Capsules are available as clear gelatin capsules or in a variety of colors. The pharmacist can use the different colored capsules to distinguish two capsule formulations for the same patient, or to encapsulate unattractive ingredients. The pharmacist can add a dye to the powder before filling a clear capsule to impart a color for identification or esthetics.

Some types of hard gelatin capsules have a locking cap, which makes it more difficult to reopen the capsule.

To aid in the selection of the appropriate size, a table, with the capacity of five common drugs for that particular size capsule, is printed on the box of the capsules. As a guide, the relative sizes and fill capacities of capsules are given below. By knowing the bulk density of fill material, proper choice of capsule size is usually made easier; however, trial and error soon develops the judgment of the beginning pharmacist.

Capsule size	Volume (ml)	Mg of Lactose	Mg of Aspirin
000	1.37	1340	1000
00	0.95	929	600
0	0.68	665	500
1	0.50	489	300
2	0.37	362	250
3	0.30	293	200
4	0.20	195	125
5	0.13	127	60

"Punch" Method of Compounding Capsules

To hand fill capsules at the prescription counter, the pharmacist generally uses the "punch" method. The ingredients are triturated to the same particle size and then mixed by geometric dilution. The powder is placed on a powder paper or ointment slab and smoothed with a spatula to a height approximately half the length of the capsule body. The base of the capsule is held vertically and the open end is repeatedly pushed or "punched" into the powder until the capsule is filled; the cap is then replaced to close the capsule. Each filled capsule is weighed using an empty capsule as a counterweight. Powder is added or removed until the correct weight has been placed in the capsule. The filled capsule is tapped so that no air spaces are visible within the contents.

It is a good practice to remove from the stock container the exact number of empty capsules needed before you begin filling them. In this way you avoid preparing the wrong number of capsules and at the same time avoid contaminating the empty capsules with drug particles that cling to your hands. Also, since some fill material will likely be lost in the process of punching capsules, the pharmacist generally calculates for the preparation of at least one extra capsule to insure enough fill for the last capsule.

The simplest method by which a capsule may be kept free of moisture during compounding is to wash the hands well, dry them, and keep the fingers dry by stripping a towel through the cleansed fingers until warmth is felt. An alternative method is to use the base of one capsule as a holder for other bases during the filling operation. The capsules do not come in contact with the fingers. The most sure method of protecting the capsule is to wear finger cots or rubber gloves.

Video demonstration of capsule punching How to pack a capsule

Capsule Machines Capsule machines are available for filling 50, 100, and 300 capsules at a time. Each manufacturer's machine is slightly different in its operation, but the series of operations is the same. Capsules are first loaded into the machine. Most machines come with a capsule loader which correctly aligns all of the capsules in the machine base. There are plates on the machine base that can be adjusted. First, the plates are adjusted to hold the capsule bodies in place while the caps are removed all at one time. The caps remain in place in the top of the machine for later use. Then the plates are adjusted again so that the capsule bodies will "drop" into place so that the tops are flush with the working surface of the plate.

The formulation powder is poured onto the plate and special spreaders and combs are used to fill the individual capsules. Some manufacturer's have special shakers that will also help spread the powder and fill the capsules. The powder is spread evenly over the plate, and the comb is used to tamp and pack the powder into the capsules. These two processes are repeated over and over again until the capsule bodies are filled with the powder. All of the caps are then simultaneously returned to the capsule bodies, and the closed capsules are removed from the machine.

The machine has the advantage of filling many capsules in a timely manner. However, there is a tendency to pack the capsules in the middle of the plate with more powder than the capsules along the periphery. It takes practice to ensure that each capsule has the same amount of drug. A quality control procedure should be executed with each batch of capsules produced with the machine.

Final Processing Once the capsules have been compounded and the capsule closed, the pharmacist may want to "seal" the capsule. The best way is to use "locking" capsules, where the body and cap lock together, making it very difficult to open the capsule again. If using locking capsules, during the filling process the cap is not completely closed onto the body in the weighing procedure to determine the weight of powder in the capsule. The locking is done only one time and that is after the capsule is correctly filled.

If locking capsules are not used, a seal can be made by touching the outer edge of the body with a moist towel to soften the gelatin. Alternatively, a cotton swab dipped in warm water can be rubbed around the inner edge of the cap. When the cap is closed on the body, it is slightly twisted to form the seal.

When compounding and sealing are complete, the capsules may need cleaning to remove fingerprints, traces of body oils, or loss powder from the capsule. Fingerprints and oils cannot be effectively cleaned from capsules so the best way to prevent these problems is to wear gloves during the compounding process. Any clinging powder can be removed by rolling the capsules between the folds of a towel.

Another proposed cleaning method is to put the capsules in a container filled with sodium bicarbonate, sugar, or sodium chloride, and gently roll the container. Then the container contents can be poured into a ten-mesh sieve where the "cleaning salt" will pass through the sieve.

Capsules should be visually inspected and checked for:

Uniformity - check capsules for uniformity in appearance and color.
extent of fill - check capsules for uniformity of extent of fill to ensure that all capsules have been filled.
locked - check capsules to ensure that they have all been tightly closed and locked.

Quality Control Section <795> of the USP 24/NF19 Supplement 1 requires that the capsule, "shall not be less than 90% and not more than 110% of the theoretically calculated weight of each unit." This "weight variation" requirement (discussed in Section <905> of the USP 24/NF19) measures the variability in the amount of powder contained in each capsule. This procedure can be carried out in all pharmacies.

The other Dosage Form Uniformity test of Section <905> is "content uniformity" which measures the variability in the amount of active drug contained in each capsule. Most pharmacies are not equipped to carry out content uniformity analyses since special analytical equipment is required.

It is possible to have capsules that pass the weight variation requirement but not have content uniformity. This can occur if the material put into the capsules is not a homogenous mixture of all the ingredients. Some capsules would then have more active drug than other capsules. Appropriate mixing (i.e., geometric dilution) of all capsule ingredients into a homogenous mixture before filling the capsules. In this manner, the weight variation data will be sufficient to ensure the quality of the capsules.

Additional Considerations Capsules are made of gelatin, sugar, and water and contain about 10% to 15% moisture. Gelatin can absorb up to ten times its weight in water. So if gelatin capsules are placed in areas of high humidity, they will become malformed or misshapened as they absorb moisture. On the other hand, if capsules are placed in low humidity, they become dry and brittle and may crack. To protect capsules from the extremes of humidity, they should be dispensed in plastic or glass vials and stored in a cool, drug place. It appears that a storage relative humidity of 30% to 45% is best. Cotton can be placed in the top of the vial to keep the capsules from rattling.

If powders that are being mixed before encapsulation are very light and fluffy and "difficult to manage," add a few drops of alcohol, water, or mineral oil. As an alternative, mix these powders in a plastic bag. If the powders seem to have a "static charge," use about 1% sodium lauryl sulfate.

Magnesium stearate (less than 1%) can be added to powders to increase their "flowability" which makes filling capsules easier. However, magnesium stearate is a hydrophobic compound and may interfere with the dissolution of the powders.

Controlled Release Capsules

Hydroxypropylmethylcellulose, or Methocel, is a cellulose derivative polymer that is used as a hydrophilic matrix material. When Methocel hydrates, it forms a gel of such consistency that drug diffusion through the gel can be controlled. A hydrophilic matrix controlled release system is a dynamic system composed of polymer wetting, polymer hydration, and polymer dissolution. At the same time, other soluble excipients or drugs will also wet, dissolve, and diffuse out of the matrix while insoluble materials will be held in place until the surrounding polymer erodes or dissolves away.

Initially, the surface becomes wet and Methocel polymer starts to partially hydrate forming a gel layer on the surface of the capsule. As water continues to permeate into the capsule, the gel layer becomes thicker, and soluble drug will diffuse out through the gel layer. Ultimately, water will dissolve the capsule shell and continue to penetrate into the drug core. So release is controlled by the dissolution of soluble drug into the penetrating water and diffusion across the gel layer.

To formulate a successful hydrophilic matrix system, the polymer substance must wet and hydrate to form a gel layer fast enough to protect the interior of the capsule from dissolving and disintegrating during the initial wetting and hydration phase. If the polymer is too slow to hydrate, gastric fluids may penetrate to the capsule core, dissolve the drug substance, and allow the drug to diffuse out prematurely. Even among the family of hydroxypropylmethylcellulose products (Methocel E, F, and K), there are significant differences in the rate at which the polymers will hydrate. This is due to the varying proportions of the two chemical substituents attached to the cellulose backbone, hydroxypropoxyl and methoxyl substitution.

The methoxyl substituent is a relatively hydrophobic component and does not contribute as greatly to the hydrophilic nature of the polymer and the rate at which it will hydrate. The hydroxpropoxyl group does contribute greatly to the rate of polymer hydration. As a result, Methocel K products are the fastest to hydrate because they have the lower amount of the hydrophobic methoxyl substitution and a higher amount of the hydrophilic hydroxypropoxyl substitution. The range of chemical substitution in Methocel products is shown below.

Product	% Methoxyl	% Hydroxypropoxyl	% Hydroxypropoxyl
Methocel K	19-24	7-12	Fastest
Methocel E	28-30	7-12	Next Fastest
Methocel F	27-30	4-7.5	Slow
Methocel A	27.5-31.5	0	Slowest

Increasing the concentration of the polymer in a matrix system increases the viscosity of the gel that forms on the capsule surface. Therefore, an increase in the concentration of the polymer used will generally yield a decrease in drug diffusion and drug release. An increase in the concentration of polymer also tends to put more polymer on the capsule surface. Wetting is more readily achieved so gel formation is accelerated.

TOPIC FIVE: Emulsions and creams

Introduction An emulsion is a thermodynamically unstable two-phase system consisting of at least two immiscible liquids, one of which is dispersed in the form of small droplets throughout the other, and an emulsifying agent. The dispersed liquid is known as the internal or discontinuous phase, whereas the dispersion medium is known as the external or continuous phase. Where oils, petroleum hydrocarbons, and/or waxes are the dispersed phase, and water or an aqueous solution is the continuous phase, the system is called an oil-in-water (o/w) emulsion. An o/w emulsion is generally formed if the aqueous phase constitutes > 45% of the total weight, and a hydrophilic emulsifier is used. Conversely, where water or aqueous solutions are dispersed in an oleaginous medium, the system is known as a water-in-oil (w/o) emulsion. W/O emulsions are generally formed if the aqueous phase constitutes < 45% of the total weight and an lipophilic emulsifier is used.

Emulsions are used in many routes of administration. Oral administration can be used, but patients generally object to the oily feel of emulsions in the mouth. But some times, emulsions are the formulation of choice to mask the taste of a very bitter drug or when the oral solubility or bioavailability of a drug is to be dramatically increased.

More typically, emulsions are used for topical administration. Topical emulsions are creams which have emollient properties. They can be either o/w or w/o and are generally opaque, thick liquids or soft solids. Emulsions are also the bases used in lotions, as are suspensions. The term "lotion" is not an official term, but is most often used to describe fluid liquids intended for topical use. Lotions have a lubricating effect. They are intended to be used in areas where the skin rubs against itself such as between the fingers, thighs, and under the arms.

Emulsions are also used a ointment bases and intravenously administered as part of parenteral nutrition therapy. Their formulation and uses in these roles will be covered in the appropriate chapters.

The consistency of emulsions varies from easily pourable liquids to semisolid creams. Their consistency will depend upon:

the internal phase volume to external phase volume ratio
in which phase ingredients solidify
what ingredients are solidifying

Stearic acid creams (sometimes called vanishing creams) are o/w emulsions and have a semisolid consistency but are only 15% internal phase volume. Many emulsions have internal phases that account for 40% - 50% of the total volume of the formulation. Any semisolid character with w/o emulsions generally is attributable to a semisolid external phase.

W/O emulsions tend to be immiscible in water, not water washable, will not absorb water, are occlusive, and may be "greasy." This is primarily because oil is the external phase, and oil will repel any of the actions of water. The occlusiveness is because the oil will not allow water to evaporate from the surface of the skin. Conversely, o/w emulsions are miscible with water, are water washable, will absorb water, are nonocclusive, and are nongreasy. Here water is the external phase and will readily associate with any of the actions of water.

Emulsions are, by nature, physically unstable; that is, they tend to separate into two distinct phases or layers over time. Several levels of instability are described in the literature. Creaming occurs when dispersed oil droplets merge and rise to the top of an o/w emulsion or settle to the bottom in w/o emulsions. In both cases, the emulsion can be easily redispersed by shaking. Coalescence (breaking or cracking) is the complete and irreversible separation and fusion of the dispersed phase. Finally, a phenomenon known as phase inversion or a change from w/o to o/w (or vice versa) may occur. This is considered a type of instability by some.

Emulsifying Agents

Emulsions are stabilized by adding an emulsifier or emulsifying agents. These agents have both a hydrophilic and a lipophilic part in their chemical structure. All emulsifying agents concentrate at and are adsorbed onto the oil:water interface to provide a protective barrier around the dispersed droplets. In addition to this protective barrier, emulsifiers stabilize the emulsion by reducing the interfacial tension of the system. Some agents enhance stability by imparting a charge on the droplet surface thus reducing the physical contact between the droplets and decreasing the potential for coalescence. Some commonly used emulsifying agents include tragacanth, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and polymers known as the Spans® and Tweens®.

Emulsifying agents can be classified according to: 1) chemical structure; or 2) mechanism of action. Classes according to chemical structure are synthetic, natural, finely dispersed solids, and auxiliary agents. Classes according to mechanism of action are monomolecular, multimolecular, and solid particle films. Regardless of their classification, all emulsifying agents must be chemically stable in the system, inert and chemically non-reactive with other emulsion components, and nontoxic and nonirritant. They should also be reasonably odorless and not cost prohibitive.

Synthetic Emulsifying Agents Cationic, e.g., benzalkonium chloride, benzethonium chloride Anionic, e.g., alkali soaps (sodium or potassium oleate); amine soaps (triethanolamine stearate); detergents (sodium lauryl sulfate, sodium dioctyl sulfosuccinate, sodium docusate). Nonionic, e.g., sorbitan esters (Spans®), polyoxyethylene derivatives of sorbitan esters (Tweens®), or glyceryl esters Cationic and anionic surfactants are generally limited to use in topical, o/w emulsions. Cationic agents (quarternary ammonium salts) are incompatible with organic anions and are infrequently used as emulsifiers. Soaps are subject to hydrolysis and may be less desirable than the more stable detergents.

Natural Emulsifying Agents A variety of emulsifiers are natural products derived from plant or animal tissue. Most of the emulsifiers form hydrated lyophilic colloids (called hydrocolloids) that form multimolecular layers around emulsion droplets. Hydrocolloid type emulsifiers have little or no effect on interfacial tension, but exert a protective colloid effect, reducing the potential for coalescence, by:

providing a protective sheath around the droplets
imparting a charge to the dispersed droplets (so that they repel each other)
swelling to increase the viscosity of the system (so that droplets are less likely to merge)
Hydrocolloid emulsifiers may be classified as:

vegetable derivatives, e.g., acacia, tragacanth, agar, pectin, carrageenan, lecithin
animal derivatives, e.g., gelatin, lanolin, cholesterol
Semi-synthetic agents, e.g., methylcellulose, carboxymethylcellulose
Synthetic agents, e.g., Carbopols®

Naturally occurring plant hydrocolloids have the advantages of being inexpensive, easy to handle, and nontoxic. Their disadvantages are that they require relatively large quantities to be effective as emulsifiers, and they are subject to microbial growth and thus their formulations require a preservative. Vegetable derivatives are generally limited to use as o/w emulsifiers.

The animal derivatives general form w/o emulsions. Lecithin and cholesterol form a monomolecular layer around the emulsion droplet instead of the typically multimolecular layers. Cholesterol is a major constituent of wool alcohols and it gives lanolin the capacity to absorb water and form a w/o emulsion. Lecithin (a phospholipid derived from egg yolk) produces o/w emulsions because of its strong hydrophilic character. Animal derivatives are more likely to cause allergic reactions and are subject to microbial growth and rancidity. Their advantage is in their ability to support formation of w/o emulsions.

Semi-synthetic agents are stronger emulsifiers, are nontoxic, and are less subject to microbial growth. Synthetic hydrocolloids are the strongest emulsifiers, are nontoxic, and do not support microbial growth. However, their cost may be prohibitive. These synthetic agents are generally limited to use as o/w emulsifiers.

Finely Divided or Finely Dispersed Solid Particle Emulsifiers These agents form a particulate layer around dispersed particles. Most will swell in the dispersion medium to increase viscosity and reduce the interaction between dispersed droplets. Most commonly they support the formation of o/w emulsions, but some may support w/o emulsions. These agents include bentonite, veegum, hectorite, magnesium hydroxide, aluminum hydroxide and magnesium trisilicate.

Methods of Emulsion Preparation Commercially, emulsions are prepared in large volume mixing tanks and refined and stabilized by passage through a colloid mill or homogenizer. Extemporaneous production is more concerned with small scale methods. Several methods are generally available to the pharmacist. Each method requires that energy be put into the system in some form. The energy is supplied in a variety of ways: trituration, homogenization, agitation, and heat.

TOPIC FOUR PHARMACEUTICAL SOLUTIONS

Introduction The study of pharmaceutical solutions is essential to the practicing pharmacist and can be, at times, somewhat complex. In addition to considering the therapeutic appropriateness of the drug, the pharmacist must consider many factors regarding the chemical and physical aspects of the product. Is the drug soluble in an acceptable solvent? Is it chemically stable in solution and for how long? Are two or more solutes chemically and physically compatible in solution? How will changes in temperature, pH or light exposure affect the product? Should the product be preserved, buffered, or flavored and how? How should the product be packaged and stored?

You may be wondering if you really need to know all of these things when so many products are commercially available. Absolutely! Many oral solutions are not produced commercially because they are unstable and have a short shelf-life or are used in such a small patient population that they are unprofitable to produce commercially. Hence, you may be called upon to formulate and dispense many such products.

As with any product, safety and accuracy of dosing are our ultimate goals. Thus, you must learn to read and interpret the prescription properly, to make the necessary calculations to prepare a product of desired strength, and to use the proper judgments and formulation techniques to ensure a stable, potent product. Finally, you must learn to clearly and accurately label the products with the appropriate instructions for use. There may be times when written or verbal instructions are necessary to supplement the label directions.

A solution is a thermodynamically stable, one-phase system composed of 2 or more components, one of which is completely dissolved in the other. The solution is homogeneous because the solute, or dispersed phase, is dispersed throughout the solvent in molecular or ionic sized particles. Broadly defined, a solution may be any combination of solids, liquids, and/or gases. We will restrict our definition of pharmaceutical solutions to those composed of a solid, liquid, or gas dissolved in a liquid solvent.

The assignment of the terms solute and solvent is sometimes arbitrary. Generally, the solute is the component present in the smallest amount and the solvent is the larger, liquid component. Water is nearly always considered the solvent. Pharmaceutical solutes may include active drug components, flavoring or coloring agents, preservatives, and stabilizers or buffering salts. Water is the most common solvent for pharmaceutical solutions, but ethanol, glycerin, propylene glycol, isopropyl alcohol or other liquids may be used, depending on the product requirements. To be an appropriate solvent, the liquid must completely dissolve the drug and other solid ingredients at the desired concentration, be nontoxic and safe for ingestion or topical application, and be aesthetically acceptable to the patient in terms of appearance, aroma, texture, and/or taste.

The solubility of a drug is the expression of the quantity of a drug that can be maintained in solution in a given solvent at a given temperature and pressure. It is usually expressed as the number of milliliters of solvent required to dissolve 1 gram of the drug. Understanding drug solubility is critical in formulating solutions. This topic will be covered in more depth in a later exercise.

A saturated solution is one that contains the maximum amount of solute that the solvent will accommodate at room temperature and pressure. A supersaturated solution is one that contains a larger amount of solute than the solvent can normally accommodate at that temperature and pressure. It is usually obtained by preparing a saturated solution at a higher temperature, filtering out excess solute and reducing the temperature. Saturated and supersaturated solutions are physically unstable and tend to precipitate the excess solute under less than perfect conditions (e.g. when refrigerated or upon the addition of other additives).

A differentiation is sometimes made between solutions on the basis of solute molecular size. Micromolecular solutions consist of dispersed molecules or ions in the 1-10 A size (MW < 10,000). In macromolecular solutions (MW > 10,0000), the solutes are in true solutions, but the solute size of macromolecular solutions lends special properties to them. Because the particles are so large, most cannot be sterilized by filtration. The solutions are also quite viscous, and may be used as thickening agent for other dispersed dosage forms. Macromolecular solutions include those containing acacia, methylcellulose and other cellulose derivatives, and proteins such as albumin.

Pharmaceutical Applications of Solutions Solutions have a wide variety of uses in the pharmaceutical industry. They are used therapeutically as vehicles for oral, parenteral, topical, otic, ophthalmic, and nasal products. They are also used as flavorings, buffers, preservatives, and suspending agents for a variety of liquid dosage forms. Concentrated stock solutions often serve as components of extemporaneously prepared products. Test solutions also play an important role in the analysis of pharmaceutical products of all types.

Classification of Solutions by Solvent Type Aqueous solutions are the most prevalent of the oral solutions. Drugs are dissolved in water along with any necessary flavorings, preservatives, or buffering salts. Distilled or purified water should always be used when preparing pharmaceutical solutions.

The following are examples of aqueous pharmaceutical solutions.

Syrups are concentrated, viscous, sweetened, aqueous solutions that contain less than 10% alcohol , e.g. Syrup USP, Wild Cherry Syrup USP. Aromatic waters are saturated solutions of volatile oils in water and are used to provide a pleasant flavor or aroma, e.g. Peppermint Water, USP. Mucilages are thick, viscous macromolecular solutions produced by dispersing vegetable gums in water. They are commonly used as suspending or thickening agents, e.g. Acacia Mucilage; Tragacanth Mucilage. Aqueous acids are dilute aqueous solutions of acids (usually < 10%), e.g. Diluted HCl, USP.

Syrups Because of their prevalence as solution vehicles, we will consider some of the special qualities of syrups. A syrup is a concentrated or nearly saturated solution of sucrose in water. A simple syrup contains only sucrose and purified water (e.g. Syrup USP). Syrups containing pleasantly flavored substances are known as flavoring syrups (e.g. Cherry Syrup, Acacia Syrup, etc.). Medicinal syrups are those to which therapeutic compounds have been added (e.g. Guaifenesin Syrup).

Syrup, USP contains 850 gm sucrose and 450 ml of water in each liter of syrup. Although very concentrated, the solution is not saturated. Since 1 gm sucrose dissolves in 0.5 ml water, only 425 ml of water would be required to dissolve 850 gm sucrose. This slight excess of water enhances the syrup's stability over a range of temperatures, permitting cold storage without crystallization.

The high solubility of sucrose indicates a high degree of hydration or hydrogen bonding between sucrose and water. This association limits the further association between water and additional solutes. Hence, syrups have a lower solvent power than water and "salting out" (see Remington's [reference textbook, can be obtained from the library] for explanation) may be a problem.

Nonaqueous solutions are those solutions which contain solvents other than water, either alone or in addition to water. Alcohol or a binary mixture containing alcohol is the most commonly used nonaqueous solvent. In addition to the pharmaceutical classes of elixirs, spirits, tinctures, and fluid-extracts, individual products such as Chloroform Liniment and Coal Tar Solution are alcoholic solutions.

Elixirs Elixirs are defined by the USP as "clear, sweetened, hydroalcoholic liquids intended for oral use." Their alcohol content ranges from 5-40% (10-80 proof), e.g. Phenobarbital Elixir, USP. Elixirs are flavored hydroalcoholic solutions to which glycerin often is added to enhance the solvent properties and act as a preservative. The alcoholic contents of elixirs varies widely; actually a few commercial elixirs contain no alcohol, while other elixirs may contain as much as 40% alcohol. The concentration of alcohol is determined by the amount required to maintain the drug or volatile oil in solution. The addition of aqueous solutions to elixirs may cause turbidity or separation by lessening the alcohol concentration.

Spirits Spirits or essences are alcoholic or hydroalcoholic solutions of volatile substances (usually volatile oils) with alcohol contents ranging from 62-85% (124-170 proof). They are most frequently used as flavoring agents, e.g. Peppermint Spirit USP. Some spirits are used for their medicinal effect, but most spirits are a convenient means of obtaining a proper amount of a flavoring oil. All essences have a high alcohol content, and the addition of water invariably causes turbidity and separation.

Whisky and Brandy are prepared by distillation. Compound Orange Spirit, Camphor Spirit, and Compound Cardamon Spirit are prepared by simple solution.

Tinctures Tinctures are alcoholic or hydroalcoholic solutions prepared from vegetable or chemical substances. The concentration of solute varies up to 50%, e.g. Vanilla Tincture USP, Iodine Tincture USP. Tinctures are alcoholic solutions of nonvolatile substances which are generally extracted by maceration or percolation. Tinctures of potent drugs represent the activity of 10 g of the drug in each 100 ml of the tincture; they are 10% tinctures. With a few exceptions, nonpotent tinctures represent 20 g of the drug per 100 ml of tincture.

Tinctures are prepared chiefly by percolation and maceration. Percolation is the procedure of choice when the crude drugs are cellular in structure; plant exudates tend to become impacted in the percolator and stop the flow so that maceration is preferred in such preparations. Moderately coarse powders are preferred, because coarse powders are slowly penetrated by the menstruum and fine powders tend to clog the percolator.

Usually alcohol or a hydroalcoholic menstruum is employed. The choice of menstruum depends on the solubility, stability, and ease of removal of the desired constituent. Other inactive constituents are extracted, but if the material is not objectionable, it is allowed to remain.

In the process of percolation, the drug is dampened with the menstruum and allowed to stand for a short period before packing the percolator so that the drug may expand as the menstruum is absorbed. If the drug is packed into the percolator and moistened, the swelling would pack the drug so firmly that the percolate could not flow.

The menstruum is then added to cover the drug and the lower opening is closed when the liquid is about to drip from the percolator. This permits the air between the particles to escape as the menstruum descends. Maceration for a prescribed time permits saturation of the menstruum in contact with the drug, assuring a more nearly complete extraction.

The menstruum is then allowed to flow or percolate at a definite rate. Normally the percolate collected is assayed before final volume is reached, and then it is adjusted to the proper strength.

In the process of maceration the drug is soaked with the menstruum in a closed container. The closed container prevents the loss of volatile constituents and evaporation of the menstruum. The mixture is agitated frequently so the menstruum at the bottom of the container does not become saturated and incapable of extracting further drug. Circulatory maceration is an efficient modification which eliminates the need for agitation. When heat is employed in maceration, the process is known as digestion. The mixture is then transferred to a filter, and the residue is washed with sufficient menstruum to bring the tincture to final volume.

Preservation Examination of unofficial liquid pharmaceutical speciality products and similar official products indicates that a minimum of 15% alcohol is required to preserve the product from microbial growth if no other preservative agents are present. Industrial pharmacists usually regard 15% alcohol as adequate for the preservation of products with a pH of 5, while 18% has been considered adequate for neutral or slightly alkaline preparations. It is obvious that products such as tinctures, spirits, and fluid extracts possess alcohol in concentrations that far exceed these values and need no further preservative.

Other Nonaqueous Solutions Water Miscible Cosolvent Systems are solutions of water and water miscible solvents such as alcohol, glycerin, propylene glycol, polyethylene glycol 400. These solvent mixtures are used to improve the solubility of poorly soluble organic substances, and may be formulated for oral, topical, or parenteral administration. e.g. Phenytoin Inj.

Glycerins or Glycerites are solutions in composed of no less than 50% glycerin by weight. They are extremely viscous and are rarely used in practice and are generally limited to use in topical products, e.g. Glycerin Otic Solution.

Collodions are liquid preparations containing nitrocellulose pyroxylin in a mixture of ethanol and ethyl ether. They are used as topical protectives or as a topical drug vehicle. They are made "flexible" by the addition of castor oil, e.g. Flexible Collodion USP, Salicylic Acid Collodion USP.

Liniments are solutions of various substances in oil, alcoholic solutions of soap or emulsions which are intended for external application, e.g. Ben Gay.

Oleaginous Solutions are solutions of fat soluble vitamins (Vitamin A, O, and E), or other fat soluble substances in vegetable oils (corn, cottonseed, olive, peanut, and sesame seed oils) or mineral oil. Oleaginous solutions may be formulated for oral, topical or parenteral administration.

The nonpolar solvents used in pharmacy are essentially hydrocarbons or glyceryl esters. Peanut, sesame, corn, cottonseed, and mineral oil are most frequently chosen as solvents or vehicles.