Basics of Compounding With Organic Salts

Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Edmond, Oklahoma

It is important to know what chemical form of a drug is used for "dosing." Many drugs are "salts" and the dose may be based on the total salt form the base form, or the acid form of the drug. The purity and form of all ingredients used in compounding, especially of active pharmaceutical ingredients (APIs), must be known and considered during formulation. If a number of factors are not considered, the final compounded preparation may not fall within the strength requirements (e.g., 90% to 110% for compounded preparations or the United States Pharmacopeia [USP] monographs).

Background
Sources of information that can be used to determine the "form" (i.e., base, acid, salt, ester) of the drug if it is commercially manufactured would be the commercial products; also, the United States Pharmacopeia-National Formulary can be used. For example, Albuterol Sulfate Tablets USP are based on the "albuterol" content (present as the sulfate form). The USP states, "Albuterol Tablets USP contain an amount of albuterol sulfate equivalent to not less than 90.0 percent and not more than 110.0 percent of the labeled amount of albuterol (C₁₃H₂₁NO₃)." In other words, sufficient albuterol sulfate is present to provide the labeled amount of the albuterol base.

Example:
A prescription calls for 10 mL of fentanyl 50 mcg/0.1 mL (as the citrate) topical gel. How much fentanyl citrate will be required?

1. 50 mcg/0.1 mL = X mcg/10 mL        X = 5 mg
2. Fentanyl MW = 336.47
   Fentanyl citrate MW = 528.59
3. 336.47/5 mg = 528.59/X        X = 7.85 mg
4. Each mg of fentanyl equals 528.59/336.47 = 1.57 mg fentanyl citrate

In another scenario, Diphenhydramine Hydrochloride Capsules USP are based on the total molecule (i.e., diphenhydramine hydrochloride). The USP states" Diphenhydramine Hydrochloride Capsules USP contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of diphenhydramine hydrochloride (C₁₇H₂₁NO.HCl)." As one can see, the weight of the "HCl" is considered in the dose of the drug.

Example:
A prescription calls for 30 capsules of diphenhydramine hydrochloride 35 mg each. How much diphenhydramine hydrochloride will be required?

1. Since the total salt molecule is part of the dose:
2. 30 × 35 mg = 1.05 g of diphenhydramine hydrochloride is required.

Because many drugs are either weak acids or weak bases and have limited water solubility, they are often used as their "salts" to increase their aqueous solubility. For example, sodium salts are often made from weak acids (sodium salicylate is the salt of the weak acid-salicylic acid, and a strong base-sodium hydroxide). Also, a salt such as ephedrine hydrochloride can be prepared between a weak base-ephedrine and a strong acid-hydrochloric acid. Third, the combination of a weak base-codeine and a weak acid-phosphoric acid can be used, as in codeine phosphate.

When salts are placed in an aqueous environment, they will dissolve to some extent, based upon their solubility in the aqueous media and the pH of the media. There will be a portion of the drug that is dissolved and some may remain undissolved. Of the dissolved portion, there will be a part that is "ionized" and the remainder will be "unionized," depending upon the pH of the media. Generally, it is the "unionized" portion of the drug in solution that will be absorbed for systemic effect. This is described by the "dissociation constant" or "pK_a" of the drug.

As is evident from this discussion, the purpose of the "salt" form is usually to enhance the solubility of the drug, but it may also enhance the stability and change other attributes of the drug that make it easier to handle and manipulate for producing dosage forms.

One can also see that it is only the "unionized" portion of the drug that will ultimately exert its effect in the body, as the remainder of the salt molecule may no longer follow the base, or unionized, form of the drug into the body.

Development of the Problem
The question is, why do we have some drugs that are dosed on the "base" form of the drug (whether they be weak acids or weak bases), and some drugs that are dosed on the total weight of the "salt" form of the drug?

In reviewing the USP revisions, it appears this has always been an issue with no apparent basis for which way the salts are dosed. However, both the official monographs and the FDA-approved drug products appear to be inconsistent in how they determine how a drug is dosed. Pharmacists involved in compounding must be aware of the correct use of the verbiage, as follows.

USP XII (1942) lists about 20 tablet monographs that are all based on the "salt" form of the drug. For example, Morphine Sulfate Tablets USP contain not less than 93% and not more than 107% of the labeled amount of morphine sulfate [(C₁₇H₁₉O₃N)₂.H₂SO₄.5H₂O].

USP XVI (1960) monograph for Amodiaquine Hydrochloride Tablets USP states "Amodiaquine Hydrochloride Tablets contain an amount of amodiaquine hydrochloride (C₂₀H₂₂ClN₃O.2HCl.2H₂O) equivalent to not less than 93% and not more than 107% of the labeled amount of amodiaquine base (C₂₀H₂₂ClN₃O)." It is evident in this monograph that the dose is calculated on the "base" form of the drug.

Resolution of the Problem
It is the responsibility of the formulator (compounding pharmacist) to determine whether or not the base/acid or salt form of the drug is to be used in the calculations for the amount of API to actually be used. It should be routine procedure when receiving a prescription to correctly determine whether or not the salt or base/acid form of the drug is to be used as the basis for the dose. Resources include the USP, the product package insert, and a call to the manufacturer or physician as appropriate. The included Table shows some examples of various USP articles and the form used as the basis of the label content.

Source: Allen LV, Jr. Basics of compounding with organic salts. IJPC 2010; 14(4): 322-326.

*Liquids include, but are not limited to: oral solutions, suspensions, emulsions, elixirs, syrups, ophthalmics, nasals, otics.

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