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22 Pharmaceutical Technology ® | BioPharm International ® Trends in Manufacturing May 2025 PharmTech.com COMPOUNDING compounding organizations to utilize sterile drugs when compounding sterile dosage forms (31). Drug evaluation. Drug information and labeling may be confusing, inconsistent, or have unusual formats; approved labeling may have been formatted before the USP salt policy became official. Practitioners may incor- rectly assume differences between active moieties and drugs are inconsequential; drug dosage errors in salt drugs will depend on the respective molecule masses of active moiety and counterion. Worst-case molecule structure affecting dosing would be a small molecular weight active moiety and a large inactive counterion (sulfate, phosphate, mesylate, etc.). Depending on drug properties, even small-molecule counterions (hydrogen, sodium, potassium) may be significant; the phenytoin package insert cautions that phenytoin and sodium phe- nytoin have an 8% difference in dosage effects (32). Even when clinical effects are calculated to be minimal; cal- culations will be incorrect if the counterion molecular weight is overlooked: • Drug overdose. Drug overdoses occur when a drug exception is erroneously calculated to pro- vide the active moiety amount as directed by the USP salt policy (i.e., salt policy is followed when it is not appropriate). For example, if codeine 30 mg was ordered and codeine phosphate drug amount was calculated as a new drug, the co- deine phosphate calculated value (40 mg) would be 33% high. Codeine analgesic dosage histori- cally has utilized 30 mg codeine phosphate or codeine sulfate—not codeine base (33,34). • Drug underdose. Drug underdoses occur when the drug is utilized as the active moiety with- out calculating the equivalent active moiet y amount. For example, if clopidogrel 75 mg was ordered for compounding, but clopidogrel bisul- fate was used, the clopidogrel active moiety dose (58 mg) would be 23% low. Individual compounded dosage forms must be cor- rectly labeled ref lecting the active moiety and drug content. Labeling "codeine" when dosage and content is "codeine phosphate" is not accurate. Label space limitations may encourage labeling shortcuts that are inaccurate and incorrect. The Institute for Safe Medication Practices (ISMP) has identified labeling problems in compounded dosage forms and has rec- ommended increased FDA guidance on compounded dosage form labeling (35). Drug shortages causing purchase of uncommon concentrations (e.g., hepa- rin) have contributed to errors including fatalities (36) when personnel do not recognize concentration changes and do not recalculate drug amounts. Labeling variation. Compounding personnel must be wary of inconsistent, confusing, or non-standard TABLE I. Commercial products labeling variation. Primary label Secondary label (side panel) Comment Metoprolol Succinate Extended- Release Tablets, USP, 50 mg. Each tablet contains 47.5 mg metoprolol succinate equivalent to 50 mg metoprolol tartrate, USP. Labeling to facilitate conversion from tartrate (immediate release) to succinate (extended release) Metoprolol Succinate Extended- Release Capsules, 50 mg. Each extended-release capsule contains 20.48 mg of metoprolol free base, present as 47.5 mg of metoprolol succinate and equivalent to 50 mg of metoprolol tartrate USP. Free-base molarity calculation in secondary label. Metoprolol Tartrate Tablets, USP, 25 mg. Each film-coated tablet contains metoprolol tartrate, 25 mg. No mention of metoprolol succinate. Potassium Phosphates K+ Injection, USP 45 mM P/15 mL (3 mM P/mL) 66 mEq K+/15 mL (4.4 mEq/mL) Each mL contains monobasic potassium phosphate anhydrous, 224 mg; potassium phosphate dibasic anhydrous, 236 mg equivalent to 170.3 mg potassium and 285 mg phosphate. 7.4 mOsmol/mL (calc). P and K describe elemental content on primary label mM unit of measure on primary label Potassium Phosphates K+ Injection, USP Phosphorus 45 mmol/15 mL (3 mmol/mL) Potassium 66 mEq/15 mL (4.4 mEq/mL) Each mL contains monobasic potassium phosphate anhydrous, 224 mg; potassium phosphate dibasic anhydrous, 236 mg equivalent to 170.3 mg potassium and 285 mg phosphate. 7.4 mOsmol/mL (calc). Potassium and phosphorous fully written. mmol conventional unit of measure Succinylcholine Chloride Injection USP 200 mg/10 mL (20 mg/mL) Also contains 1.8 mg methylparaben and 0.2 mg propylparaben as preservatives, 4.70 mg sodium chloride as iso-osmotic agent, and NaOH and HCl as pH adjusters, pH 3.0 to 4.5. No drug content on secondary label Other ingredients with milligram amounts per 10 mL vial. Succinylcholine chloride Injection USP 1000 mg TOTAL (100 mg/mL) May contain HCl and/or NaOH for pH adjustment. pH 3.6 (3.0 to 4.5) Sterile; non-pyrogenic. No drug content amount on secondary label.