Salt-to-Base Conversion Factor

Salt-to-Base Conversion Factor (SBF) is the dimensionless ratio of the molecular weight of the salt form supplied to the molecular weight of the free-base (or alternate-basis) form named on the label. The math is one line: SBF = MW(salt) ÷ MW(base), and adjusted target = label-claim mass × SBF. A label of 50 mg metoprolol (expressed as free base, MW 267.36) dispensed as metoprolol tartrate (MW 684.81 for the (C₁₅H₂₅NO₃)₂·C₄H₆O₆ 2:1 salt) requires 50 × 684.81/534.72 = 64.04 mg of the tartrate per dose unit to deliver 50 mg of free base.

The conversion exists because most APIs are dosed therapeutically as the free base or free acid (that is the molecule the patient's receptor recognises) but supplied physically as a salt (because the salt has better crystallinity, solubility, stability, bioavailability, or processability than the free form). The label claim is the patient contract: the prescribed dose is the active mass of the free base, and the dispense math must convert that contract into the physical mass of the salt the operator actually weighs.

The simplest case is a 1:1 salt — one molecule of the base associated with one molecule of the counterion (sodium phenytoin, prazosin HCl, sertraline HCl). The MW(salt) is the sum of the base + the counterion (minus 1 hydrogen for amine-HCl pairs), and SBF is a simple ratio. Real salt-form chemistry includes 2:1, 1:2, and unusual stoichiometries that change the MW(salt) and therefore the SBF significantly. Misreading the stoichiometry produces a doubled or halved SBF — i.e. a 50–100% silent dispense error.

• 2:1 base:acid salts — atorvastatin calcium, metoprolol tartrate, amlodipine besylate (no, amlodipine besylate is 1:1; metoprolol tartrate is 2:1 — two metoprolol molecules per tartrate). MW(salt) accounts for both base molecules and the single counterion. Treating it as 1:1 halves the apparent SBF and the dispense is half the required mass.
• 1:2 base:acid salts — e.g. quinidine sulphate dihydrate has a 2:1 quinidine:sulphate ratio in some monographs and 1:1 in others; bisoprolol fumarate is 2:1 (two bisoprolol per fumarate). Citric-acid 1:1 / 1:2 / 1:3 stoichiometries (citrate is tribasic) shift MW(salt) significantly.
• Hydrates and solvates — calcium trihydrate, sulphate heptahydrate, magnesium dihydrate. The water of crystallisation is part of MW(salt) and must be included if the supplied material is the hydrate. A 'sertraline HCl' supply might be the anhydrous form (MW 342.69) or the dihydrate (MW 378.72) — using the wrong MW gives a 9.5% error.
• Hemi-, sesqui-, and mixed-salt forms — calcium hemi-besylate, sodium sesqui-decanoate, magnesium-1.5-hydrate. Specialist forms used for solubility/stability, with non-integer stoichiometry. Read the supplier monograph exactly — never round or assume.

When SBF combines with the per-lot corrections (PF, LOD) and the formulation-level corrections (overage, counter-balance), the order matters because rounding errors compound and because each correction operates on a different basis. The canonical order, derived from EU GMP Ch.5 §5.40 and from FDA precedent in dispense audit findings:

1. Label-claim mass per dosage unit × planned batch dose count → total label-claim mass per batch (the contract with the patient, expressed on the labelled basis — free base, salt form, free acid, whichever the label names).
2. Add stability overage and manufacturing overage → as-formulated label-claim mass (still on the labelled basis).
3. Apply SBF (multiply by MW(salt) ÷ MW(base)) to convert from the labelled basis to the salt-form basis (the basis the supplier ships and the operator weighs on) → as-formulated salt-form mass.
4. Apply LOD compensation (divide by 1 − LOD) to convert from anhydrous-basis to as-is basis if the supplier assay is reported anhydrous → as-formulated as-charged mass.
5. Apply PF (multiply by reference potency ÷ measured potency) to correct for batch-to-batch potency variability → adjusted-as-charged mass. This is the figure the operator actually weighs.
6. Recompute counter-balance excipient → diluent's adjusted target so total batch mass holds.

1. Free-base label, salt-form API, SBF skipped — the textbook failure. Batch is silently under-strength by (MW(salt) − MW(base)) / MW(salt). For metoprolol tartrate that's 21.9%. Patient gets 39 mg labelled as 50 mg.
2. 2:1 stoichiometry treated as 1:1 — MW(salt) halved (or doubled, depending on direction), dispense is off by ~30–50%. Specific to atorvastatin calcium, metoprolol tartrate, bisoprolol fumarate, and similar 2:1 base:counterion pairs.
3. Anhydrous vs hydrate form mismatch — supplier ships sertraline HCl dihydrate, item master expects anhydrous; SBF based on anhydrous MW under-counts the water in the actual material, dispense is 8–10% under-strength.
4. Supplier switched salt form silently — sourcing change from atorvastatin calcium to atorvastatin magnesium without CoA flag and without change control. New material has different MW(salt), different SBF, different dispense; old SBF still in use until the first finished-product assay surfaces it.
5. Reference standard mismatch — release assay run against free-base reference standard while the as-dispensed material is the salt; assay result skewed by the SBF; finished-product spec passes by coincidence; investigators trace the error months later.
6. Operator override on the kiosk — an experienced operator 'corrected' the SBF-adjusted target back to label claim because 'the math looked wrong'; supervisor approved the override; entire batch is under-strength. Override governance was the controlling failure.
7. Label-claim basis ambiguous on legacy MMR — older MMR doesn't state whether label claim is free base or salt; production assumes one, formulation development assumed the other; quietly under- or over-strength batches for years.
8. Co-administration error — a fixed-dose combination product where both APIs are salt forms but the SBF is applied to only one; the second active is dispensed at label-claim mass without conversion; combination product fails finished-product assay for one of the two actives.

• SBF coverage % — fraction of salt-form actives where the item master holds salt form, MW(salt), MW(base), and label-claim basis (target 100% for salt-form actives).
• Salt-form identity verification % — fraction of receipts where the supplier CoA's declared salt form matches the item-master spec (target 100%; mismatch is a deviation).
• SBF override rate — fraction of dispense events where an operator or supervisor overrode the computed SBF (target 0%; every override is an automatic deviation and CAPA trigger).
• Label-claim basis explicit % — fraction of MMRs where the label-claim basis (free base / free acid / salt form / specific salt) is unambiguously stated (target 100%; ambiguous basis is a sweep finding).
• Reference standard match % — fraction of release assays where the reference standard's salt form matches the as-dispensed material's salt form (target 100%; mismatch invalidates the assay).
• Stoichiometry-correct rate — fraction of 2:1 / 1:2 / non-1:1 stoichiometry items where the MW(salt) is verified against the supplier monograph + dossier + pharmacopoeial reference (target 100%; verified annually).
• Supplier salt-form change detection time — average days between a supplier silently switching salt form and detection (target ≤30 days via CoA auto-diff; longer is a supplier-scorecard escalation).

1. Item master holds: salt_form (e.g. 'tartrate', 'calcium trihydrate', 'besylate'), mw_salt, mw_base, label_claim_basis ('free_base' | 'free_acid' | 'salt' | 'specific_salt'), salt_stoichiometry (base:counterion ratio, defaults 1:1 but explicit for 2:1 / 1:2 / hemi / sesqui), and a reference link to the pharmacopeial monograph or NDA Module 3.
2. SBF is computed deterministically: SBF = mw_salt / (mw_base × salt_stoichiometry_base) — never typed in by hand. The kiosk and the BMR both render the math.
3. Lot master CoA import auto-verifies the supplier's declared salt form against item-master salt_form; mismatch blocks lot release until QA disposition.
4. Dispense kiosk shows the label-claim mass, the SBF-converted mass (with the math visible: '50.000 kg × 684.81/534.72 = 64.04 kg salt-form'), then LOD, then PF, then counter-balance. Operator weighs to the last figure.
5. SBF override on the kiosk requires a deviation reason, supervisor e-signature, and triggers an automatic CAPA if overrides exceed 1% of dispense events.
6. BMR renders the salt-form math contemporaneously: salt form used, MW(salt), MW(base), stoichiometry, SBF, label-claim target, salt-form target, and operator + verifier signatures. A regulator can reconstruct the conversion from the BMR alone.
7. Two-person e-signature gates the dispense (Part 11 §11.50 + §11.70); the verifier sees the same math the operator weighed to.
8. Supplier salt-form change detection: incoming CoAs are auto-diffed against the previous CoA from the same supplier item — any change in declared salt form triggers a deviation before lot release.
9. Yield reconciliation at batch close uses the SBF-converted theoretical, not label-claim mass — §211.103 variance is computed correctly.
10. Periodic review (quarterly per ICH Q10 §3.2.5) audits SBF coverage, basis-explicit MMRs, and stoichiometry-correctness across the portfolio; gaps route through change control.

See the FAQs below for short answers on common operational questions — when SBF is mandatory, how to handle ambiguous label-claim basis on legacy MMRs, what happens when the supplier switches salt form, and whether SBF applies to supplements and consumer products.