Loss on Drying (LOD)

A certificate of analysis (COA) that reads "Loss on drying: 0.5%" tells you less than it seems to. Testosterone cypionate and methyltestosterone are both steroid active pharmaceutical ingredients (APIs), yet their limits in the United States Pharmacopeia editions read for this entry are 0.5% and 2.0%, set under different drying conditions.

Three kinds of reader use the term. An analyst running the weighing-bottle test (a covered glass bottle in which the sample is weighed before and after drying) needs the procedure. A formulator correcting a batch needs the effect on potency. A buyer comparing quotes needs to know whether the number is water, and what it costs in active ingredient. They often talk past each other because the percentage looks the same in every case.

This entry gives the definition and formula, the rules that make a result reproducible, the difference from water content by Karl Fischer titration, and a clause to paste into a quote request. The limits quoted come from published monographs, and each states the edition it was read from.

The United States Pharmacopeia (USP) chapter <731> defines it as "the amount of volatile matter of any kind that is driven off under the conditions specified" (USP 35 <731>).

LOD % = (W_before − W_after) ÷ (W_before − tare) × 100, where W is the weight of bottle plus sample.

Dividing by the filled bottle's weight instead of the sample's is an easy slip to make.

The same percentage means different things under different conditions, so a monograph always pairs the limit with temperature, time and apparatus. The table compares four monographs, linked in the sources list.

Limits are as printed in the editions named, read in October 2026. The three steroid APIs and one oral API shown come from monograph pages that could be read in full; this is a comparison of four monographs, not a survey.

Chapter <731> also fixes the procedure (USP 35 <731>):

• Use a 1 to 2 g specimen, with large particles crushed to about 2 mm.
• Pre-dry the weighing bottle for about 30 minutes under the same conditions.
• Spread the sample to about 5 mm deep, never more than 10 mm.
• Hold the temperature within ±2° of the stated figure.
• Close the bottle promptly and cool it in a desiccator before weighing.
• If the substance melts below the drying temperature, first hold it 1 to 2 hours at 5 to 10° below its melting point.

USP posted a Notice of Intent to Revise <731> on 28 June 2024 as an in-process revision, aimed at allowing modern technologies such as moisture analyzers (USP notice).

The European Pharmacopoeia (Ph. Eur.) names its own modes, such as "in vacuo" at 1.5 to 2.5 kilopascals (kPa) (Ph. Eur. 7.0, 2.2.32).

"Dried to constant weight" means two consecutive weighings differ by no more than 0.50 mg per gram of substance taken, the second after an additional hour of drying (USP General Notices). The rule sits in the General Notices, not in each monograph, which is why it is hard to find. It applies only when the monograph uses that phrase. Otherwise you dry for the stated time.

With a 2.0000 g specimen the allowance is 1.00 mg. Weighings of 31.4262 g and then 31.4258 g differ by 0.4 mg: pass. Weighings of 31.4262 g and 31.4245 g differ by 1.7 mg: dry another hour. It is not a 10% tolerance on the specification, and it is not a check that the bottle has cooled. The desiccator step handles cooling.

No. LOD counts everything that leaves on heating, while Karl Fischer (KF) titration reacts chemically with water only. USP <921> reserves the "Loss on drying" heading for cases where "the loss sustained on heating may be not entirely water" (USP 29 <921>).

For new drug substances, the International Council for Harmonisation (ICH) guideline Q6A says LOD "may be considered adequate; however, a detection procedure that is specific for water (e.g., Karl Fischer titration) is preferred" (ICH Q6A).

Where residual solvent or a hydrate is plausible, LOD and KF water are best reported separately. Any gap between them should be explained in writing, naming the solvent or other volatile. Residue on ignition is a different test again, listed as its own line, such as ≤0.2% for testosterone cypionate (USP 35 monograph).

Potency as received falls by the LOD, because volatiles carry no active ingredient. As-is potency = dried-basis assay × (1 − LOD ÷ 100), because the assay is expressed on the dried material. This is a model, not an official figure, using USP 35 values:

• Testosterone cypionate: 97.0% × (1 − 0.005) = 96.5% at the limits.
• Testosterone: 97.0% × (1 − 0.01) = 96.0%.
• A 25 kg lot at 2.0% LOD holds 0.50 kg of volatiles. Cost per kilogram of active rises by 1 ÷ 0.98 = 1.0204, about 2.04%.

The dried-basis assay range of 97.0% to 103.0% is given in USP 35. See assay on anhydrous basis for how the basis is stated.

State the method, conditions, limit and potency basis in the request, then test the COA against five checks:

1. Method and edition. Pass: it names a compendium and edition year. Fail: "LOD: 0.3%" alone.
2. Conditions. Pass: temperature, time, vacuum or desiccant, and specimen size are all printed. Fail: any is missing.
3. Limit. Pass: the result meets the monograph limit or your tighter one. Fail: the result exceeds the limit or no limit is printed.
4. Potency basis. Pass: dried-basis × (1 − LOD ÷ 100) reproduces the as-is figure within rounding. Fail: only one basis is given.
5. Water. Pass: KF water is reported, and LOD minus KF water is explained in writing (solvent or other volatile named). Fail: no KF value, or an unexplained gap.

Clause to paste: "Loss on drying per [USP <731> or Ph. Eur. 2.2.32, edition year], [temperature, time, vacuum or desiccant], not more than [x]%. Report potency on the dried basis and as received. Report water by Karl Fischer separately."

Aarise Pharmaceuticals' quote requests ask for product or Chemical Abstracts Service (CAS) number, quantity, destination, grade or purity, documents, payment terms and Incoterms (international delivery terms); the loss on drying clause goes in the documents line. It supports sample and evaluation quantities for qualified B2B buyers, subject to the API, availability and applicable regulatory requirements. COA, specifications and safety data sheets (SDS/MSDS) are available where applicable, and are confirmed product by product at enquiry. Requests go through its contact form, where phone, WhatsApp and email details are listed.