By Matt Martin, PharmD, PCCA Clinical Services Manager, and Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development

We prepared this article to guide compounding pharmacies on how to review USP monographs related to an active ingredient as well as its certificate of analysis (COA) to determine the appropriate amount of chemical to use in compounding a desired medication. It will provide considerations for pharmacies as they develop their standard operating procedures (SOPs) for their compounding practices. We will review the process of evaluating a chemical and use examples to illustrate each step. It should be noted that the examples are based on PCCA chemicals and that there can be differences in the chemicals from other vendors that may result in them having different specifications on their COAs.

In pharmacy compounding, it is necessary to understand how the strength of medications is expressed and which calculations are needed to determine the amount of any active pharmaceutical ingredient (API) in a compounded medication. In order to accomplish this, the pharmacy should have a process detailed in an SOP. Below are the general steps that the SOP should address followed by examples of applying these steps to specific chemicals.

In determining the applicability of the data from the COA of the chemical:

1. Evaluate how the strength of the compounded preparation is going to be expressed
2. Evaluate if the assay as well as water and/or solvent content (loss on drying) from the COA will need to be applied
3. Evaluate if other conversions, such as a base/salt calculation or molecular weight “fixed factor” calculation, will be needed
    

1. Evaluate how the strength of the compounded preparation is going to be expressed.

One of the best resources for understanding how the strength of drug products is expressed is the United States Pharmacopeia (USP). It sets standards for chemical quality and contains both chemical and drug product monographs that detail what the assay for those products is measuring in terms of the molecular formula of the drug. This is very helpful when determining the calculations that apply to any specific API. Reviewing the USP chemical monograph and the drug product monograph will allow you to determine if the API strength is expressed as the free base, salt form, esterified form, hydrated form, anhydrous form, etc. Compounders should therefore strongly consider having access to the full USP to be able to use both the chemical and drug product monographs. Access to the full USP is available at uspnf.com.

While the USP monographs cover most drug products and APIs, not all drug products and APIs have an official USP monograph. When a USP drug product monograph is not available, it may be necessary to review the package insert(s) of drug products to gain an understanding of how the strength of a drug product is expressed.

Different scenarios exist, one of them being a situation when no calculation is necessary. Here is an example:

Example of No Calculation Needed: Morphine Sulfate Pentahydrate

One good example is morphine sulfate pentahydrate. Here is the USP chemical monograph definition: “Morphine Sulfate contains not less than 98.0 percent and not more than 102.0 percent of (C₁₇H₁₉NO ₃)₂ · H₂SO₄, calculated on the anhydrous basis.”¹ This reveals that the assay of the chemical morphine sulfate pentahydrate is measuring the morphine sulfate content and not the morphine sulfate pentahydrate content of the chemical.

However, the USP drug product monograph provides this definition: “ Morphine Sulfate Injection is a sterile solution of Morphine Sulfate in Water for Injection. It contains NLT 90.0% and NMT 110.0% of the labeled amount of morphine sulfate pentahydrate [(C ₁₇H₁₉NO₃)₂ · H₂ SO₄ · 5H₂O] ”² (emphasis added).

This example shows that while the chemical assay measures the anhydrous morphine sulfate content of the chemical, the drug is dosed on the amount of morphine sulfate pentahydrate. Therefore, no calculation is required when compounding with morphine sulfate pentahydrate. For this reason, we have the following note on all the PCCA morphine sulfate formulas: “Dosing of Morphine Sulfate is based on the amount of Morphine Sulfate Pentahydrate therefore no calculation is required.”

2. Evaluate if the assay as well as water and/or solvent content (loss on drying) from the COA will need to be applied.

Once you know how the strength of a drug product is expressed, you can examine the API that you have and determine what calculations may need to be performed. These calculations may include accounting for the assay as well as the water and/or solvent content (loss on drying), or the use of a fixed conversion factor based on your pharmacy’s SOP.

It is important to note that there is no uniform set of calculations that can be applied to all chemicals equally. Each set of calculation considerations is specific to a particular chemical. The assay as well as the water and/or solvent content, or loss on drying, are specific to each lot number of the API and can be found on each lot’s COA.

The assay of the chemical is a measure of the potency of that lot of chemical. When a chemical assay is performed, it may be tested as it is in the container you receive, which would be the “as-is basis.” According to the General Notices of USP, “All calculations in the compendia assume an ‘as-is’ basis unless otherwise specified.”³ In the case of an assay done on the as-is basis, only the assay would be needed for calculations as opposed to the assay and water content or loss on drying.

The alternatives to “as-is” are when the assay is performed on the “anhydrous basis” or on the “dried basis.” When the assay is performed on either the anhydrous basis or on the dried basis, the chemical is exposed to conditions (such as a chemical-specific heating process) that cause any water or a volatile substance, such as a solvent involved in the manufacturing process of the chemical, to be driven out of the chemical prior to the assay being performed. When water alone is being driven out of the chemical, this will be reflected on the COA as “water” or “water determination.” When the substance being driven out is water and/or another volatile substance, this will be reflected on the COA as “loss on drying” or “LOD.” The specifics of these tests are discussed in their respective USP chapters, USP <921> Water Determination and USP <721> Loss on Drying. Using the assay and/or the water or loss on drying from the COA is one part of assuring the appropriate potency of the compounded medication.

Let’s review an example using naltrexone for evaluating the COA to calculate the appropriate amount of naltrexone HCl USP dihydrate versus anhydrous naltrexone HCl USP:

Example of Using COA to Calculate API Amount: Naltrexone HCl

Here is the naltrexone HCl USP chemical monograph definition: “Naltrexone Hydrochloride contains NLT 98.0% and NMT 102.0% of naltrexone hydrochloride (C20H23NO4 · HCl), calculated on the anhydrous, solvent-free basis.”4

The naltrexone HCl USP drug product monograph provides this definition: “Naltrexone Hydrochloride Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of naltrexone hydrochloride (C20H23NO 4 · HCl).”5

The USP naltrexone HCl chemical monograph and the naltrexone HCl tablet drug product monograph both measure the amount of naltrexone HCl. The naltrexone HCl USP chemical monograph measures the naltrexone HCl on the anhydrous and solvent-free basis. Therefore, you need to use the COA to calculate either the amount of naltrexone HCl anhydrous or dihydrate or anhydrous naltrexone HCl in compounded formulations.

Naltrexone Hydrochloride USP Anhydrous may have a limit of total solvents up to 5% (and up to 11% for the Dihydrate form) and an assay of 98 – 102% calculated on the anhydrous and solvent-free basis.  It is important that you obtain a Certificate of Analysis for your specific lot number to verify the percentage of limit of total solvents and assay (on the anhydrous and solvent-free basis).

The following is an example calculation based on Lot #C200577 with a limit of total solvents of 0.4% and an assay of 100.3% on the anhydrous and solvent-free basis.

Naltrexone Hydrochloride 1.5 mg per capsule is required in this formula.  The limit of total solvents is 0.4% for this lot.  Thus, 100% minus 0.4% yields 99.6% of anhydrous and solvent-free Naltrexone Hydrochloride.  Divide 1.5 mg per capsule by 99.6% equals 1.506 mg per capsule of Naltrexone Hydrochloride (anhydrous and solvent-free).  Since the assay is 100.3% on the anhydrous and solvent-free basis, the required amount of Naltrexone Hydrochloride USP Anhydrous will be 1.506 mg per capsule divided by 100.3% which is 1.501 mg per capsule, or 0.15 Gm for each 100 capsules.

Naltrexone HCl USP dihydrate may be used and calculated in the same manner. The difference is the variable amount of total solvent content between the anhydrous version (may be up to 5%) and the dihydrate version (may be up to 11%). Again, it is important that you obtain a COA for your specific lot number to verify the percentage of solvent content and the assay (on the anhydrous and solvent-free basis) for either chemical used. 

3. Evaluate if other conversions, such as a base/salt calculation or molecular weight “fixed factor” calculation, will be needed.

A base/salt conversion or other calculations may also be necessary to determine how much API you will need to use in a given formulation. Sometimes, using the COA to calculate the amount may consistently produce very similar results as a “fixed conversion factor” based on a molecular weight ratio. USP does not have specific guidance on the issue of using the COA versus the use of a “fixed factor” when deemed appropriate. Policies involving the decision to choose either the COA or a fixed factor should be clearly delineated in the pharmacy’s SOP, and the accompanying rationale should be explained. The most accurate method is always the use of the lot-specific COA. Each pharmacy must determine what is an acceptable cutoff if following the practice of using a fixed factor.

An example of using a fixed conversion factor based on molecular weight ratio is estradiol. Amlodipine besylate and prazosin HCl provide good illustrations of base/salt conversion as well. We present these examples below:

Example of Fixed Conversion Factor: Estradiol

The estradiol USP drug product monographs discuss how the strengths of these products are expressed: “Estradiol Tablets contain not less than 90.0 percent and not more than 115.0 percent of the labeled amount ofC₁₈H₂₄O₂.” ⁶ “Estradiol Vaginal Cream contains NLT 90.0% and NMT 110.0% of the labeled amount of estradiol (C₁₈H₂₄O₂) in a suitable cream base.”⁷

The estradiol USP chemical monograph states, “Estradiol contains not less than 97.0 percent and not more than 103.0 percent of C₁₈H ₂₄O₂, calculated on the anhydrous basis.”⁸

When you compare the USP drug product monographs to the chemical monograph, you can note that these monographs are all measuring the chemical in the same form: C₁₈H₂₄O₂. Thus, the data from the COA will apply. In the case of estradiol, the assay is measured on the anhydrous basis, so the water content from the COA will also need to be used in the calculations.

Let’s say that 0.1 Gm of estradiol is needed for a compounded formulation and that the COA for your lot of estradiol USP has an assay of 99.7% and a water content of 3.1%. The first step will be to work with the water content. The water content will be subtracted from 100% and then converted to a decimal. The amount calculated in the previous step will be divided by this decimal.

100% – 3.1% = 96.9%

96.9%/100% = 0.969

0.1 Gm/0.969 = 0.1032 Gm

The next step will be to use the assay, but it will need to be converted from a percentage to a decimal. This is done by dividing the percentage by 100%.

Assay 99.7%/100% = 0.977

The amount of (anhydrous) API needed is then divided by this decimal.

0.1032 Gm/0.997 = 0.1035 Gm

In order to have 0.1 Gm of estradiol for the formulation, it will require 0.1035 Gm of this lot number of estradiol USP.

However, upon reviewing numerous COAs for estradiol USP, you will see that application of the assay and water content will consistently require approximately 3% more API be used in each formulation. For this reason, some pharmacies choose to employ a fixed factor of 1.033 for estradiol formulations as opposed to the specifics of the COA for each lot due to this consistency. In this case, a formulation that requires 0.1 Gm of estradiol would be calculated as 0.1033 Gm of any lot of estradiol hemihydrate USP. PCCA’s formulations also use this fixed conversion factor and have the following note listed on all formulas:

“Estradiol 1 milligram is equivalent to Estradiol Hemihydrate USP 1.033 milligrams. This fixed conversion factor is based on the ratio of the molecular weight of Estradiol Hemihydrate to the Estradiol base. (You may calculate the amount of Estradiol to be used in the formulation by using the assay and water content from the C of A for your specific lot. However, do not calculate using BOTH the fixed conversion and the C of A assay & water content.) You should follow your standard operating procedure for appropriately calculating these amounts for your formulations. ”

If you consider that the difference in this example between using the COA and the fixed conversion factor was 0.0002 Gm, this is a difference of 0.2% in the final formulation. Each pharmacy must determine what is acceptable if following this practice. It is important to note that you should not calculate using both the fixed conversion and the COA assay and water content.

As another example, some pharmacies, and PCCA formulations, also use a fixed conversion factor for lidocaine HCl monohydrate. Here is the fixed conversion factor: Lidocaine HCl monohydrate 1 mg is equivalent to lidocaine HCl 0.938 mg.

Example of Base/Salt Conversion: Amlodipine Besylate

What many would call “amlodipine tablets” are found in the USP drug product monographs as “amlodipine besylate tablets.” Based on the name of the USP drug product monograph, one might believe that these tablets express their strength as the amount of amlodipine besylate. However, upon review of the amlodipine besylate tablet monograph’s definition section, one finds: “Amlodipine Besylate Tablets contain NLT 90% and NMT 110% of the labeled amount of amlodipine (C₂₀H₂₅ClN₂O ₅).”⁹ The drug product monograph shows that these tablets express their strength as the amount of amlodipine instead of the amount of amlodipine besylate. This is an important distinction when comparing it to the bulk API used to compound amlodipine oral suspension or capsules. The bulk API is amlodipine besylate (C₂₀H₂₅ ClN₂O₅ · C₆H₆O₃S), which is a salt form of amlodipine. In order to determine the amount of amlodipine besylate that is equivalent to amlodipine, we will have to employ a base/salt conversion.

A base/salt conversion is a ratio of the molecular weight of the salt form of the chemical to the molecular weight of the base form of the chemical, or vice versa. The molecular weight of amlodipine besylate (the salt form) is 567 Gm/mole. The molecular weight of amlodipine (the free base form) is 409 Gm/mole. The ratio of the molecular weights of amlodipine besylate to amlodipine is 567/409, or 1.39. This means that for every gram of amlodipine needed, the formulation will require 1.39 Gm of amlodipine besylate.

PCCA amlodipine formulations therefore use this fixed base/salt conversion: Amlodipine 1 mg is equivalent to amlodipine besylate 1.39 mg. Therefore, an amlodipine 1 mg/mL oral suspension would require 1.39 mg/mL amlodipine besylate, or 0.139 Gm for a 100 mL preparation.

Example of Base/Salt Conversion: Prazosin HCl

An example of a base/salt conversion that must also take the COA into consideration is prazosin HCl polyhydrate. The prazosin HCl USP chemical monograph provides this definition: “Prazosin Hydrochloride contains NLT 97.0% and NMT 103.0% of prazosin hydrochloride (C₁₉H ₂₁N₅ O₄ · HCl), calculated on the anhydrous basis.”¹⁰

The prazosin HCl USP drug product monograph provides this definition: “Prazosin Hydrochloride Capsules contain an amount of prazosin hydrochloride (C₁₉H₂₁N₅O₄  · HCl) equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of prazosin (C₁₉H₂₁N₅O₄).” ¹¹

The chemical monograph reveals that the assay is measuring the prazosin HCl (salt form) content; however, the drug product monograph shows the strength as prazosin (free base). In the prazosin formulas developed at PCCA, we document multiple steps of calculation to obtain the correct amount of prazosin HCl USP polyhydrate to be used in a prazosin compound: First, a salt conversion from prazosin to prazosin HCl must be done. Second, the percentage of water content may vary lot to lot from 8–15% for prazosin HCl USP polyhydrate. Third, the assay of prazosin hydrochloride USP (on the anhydrous basis) may also vary lot to lot between 97–103%

All of these need to be taken into account. As always, it is important that you obtain a COA for your specific lot number to verify the percentage of water content and the assay (on the anhydrous basis).

The following is an example calculation with a water content of 11.7% and an assay of 99.3% on the anhydrous basis.

Let’s assume prazosin 1 mg/mL is required in a suspension formula. Prazosin 1 mg is equivalent to prazosin HCl 1.095 mg. Multiplying 1 mg by 1.095 equals prazosin HCl 1.095 mg/mL that is required in this formula. The water content is 11.7%; thus, 100% minus 11.7% yields 88.3% of anhydrous prazosin HCl. Dividing 1.095 mg by 88.3% equals prazosin hydrochloride anhydrous 1.24 mg/mL.

Since the assay is 99.3% on the anhydrous basis, the required amount of prazosin HCl USP polyhydrate will be 1.24 mg/mL divided by 99.3%, which is 1.249 mg/mL, or 0.1249 Gm for every 100 mL of suspension.

As stated above, the processes and examples described in this article provide considerations for you as you develop your SOPs for your compounding practice. These examples demonstrate the need to evaluate the application of calculations to each drug individually. In addition, reviewing the USP chemical and drug product monographs when they are available provide clarity as to how the data should be applied in each case. Using these resources should help you determine the applicability of the chemical’s COA and how to accurately calculate the appropriate amount of API to use for the needed dose. Our Clinical Services department is available to work with PCCA members on these calculations and other formulation needs they may have.

Matt Martin, PharmD, is the Clinical Services Manager at PCCA. He joined the PCCA Clinical Services department in September 2014. Matt graduated from Morehead State University with a BS in Chemistry in 2002, and received his PharmD from the University of Kentucky College of Pharmacy in 2006. Prior to joining the PCCA team, Matt worked in pharmacy compounding for more than eight years, and has experience with both sterile and nonsterile preparations.

Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development, received her pharmacy degree from Mercer University in Atlanta, Georgia, in 1995. She currently is involved with and oversees the development and implementation of new formulas at PCCA. She had more than six years of compounding experience with pharmacies in Georgia and Florida prior to joining the PCCA staff in 2004. Her areas of interest include women’s health, veterinary and pain management compounding.

References

1. United States Pharmacopeial Convention. (2020). Morphine sulfate. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

2. United States Pharmacopeial Convention. (2020). Morphine sulfate injection. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

3. United States Pharmacopeial Convention. (2020). General notices and requirements. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

4. United States Pharmacopeial Convention. (2020). Naltrexone hydrochloride. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

5. United States Pharmacopeial Convention. (2020). Naltrexone hydrochloride tablets. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

6. United States Pharmacopeial Convention. (2020). Estradiol tablets. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

7. United States Pharmacopeial Convention. (2020). Estradiol vaginal cream. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

8. United States Pharmacopeial Convention. (2020). Estradiol. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

9. United States Pharmacopeial Convention. (2020). Amlodipine besylate tablets. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

10. United States Pharmacopeial Convention. (2020). Prazosin hydrochloride. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

11. United States Pharmacopeial Convention. (2020). Prazosin hydrochloride capsules. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/