Sirolimus Analogs API Comparison: Sirolimus, Everolimus, Zotarolimus, Temsirolimus, Ridaforolimus vs Tacrolimus & Cyclosporin A

Sirolimus and tacrolimus bind the same intracellular protein, FKBP12. Only one of them then blocks calcineurin. That single divergence separates two API families that are quoted in the same enquiries, filed under the same therapeutic heading and confused on the same purchase orders. The five rapalogs — sirolimus (CAS 53123-88-9), everolimus (CAS 159351-69-6), temsirolimus (CAS 162635-04-3), zotarolimus (CAS 221877-54-9) and ridaforolimus (CAS 572924-54-0) — act on mTORC1. Tacrolimus (CAS 104987-11-3) and cyclosporin A (CAS 59865-13-3) act on calcineurin. All seven descend from fermentation, all seven are high-value, and the five rapalogs combined move less API volume than the two calcineurin inhibitors beside them.

1. Seven-Way Snapshot: The Core Comparison Table

Seven compounds, three chemical classes, two molecular targets, and a commercial picture that ranges from multi-source bulk supply to a molecule that was never approved anywhere.

Two groupings matter more than any individual row. The mTOR group is the five rapalogs. The calcineurin group is tacrolimus and cyclosporin A. Nothing about the clinical or commercial behaviour of the seven makes sense until the target column is read first.

2. One Immunophilin, Two Targets: Rapalogs vs Calcineurin Inhibitors

This is the single most consequential fact in the category, and the reason enquiries mix the compounds up.

Tacrolimus and sirolimus are both macrolides, and both bind the immunophilin FKBP12 (FK506-binding protein 12). The binding step is shared. Everything after it diverges:

• Tacrolimus–FKBP12 → calcineurin. The complex binds and inhibits calcineurin, the calcium/calmodulin-dependent phosphatase that dephosphorylates NFAT and drives transcription of IL-2 and other cytokine genes. The block is upstream: T-cell activation signalling is interrupted before cytokine production.
• Sirolimus–FKBP12 → mTORC1. The complex has no effect on calcineurin activity at all. It binds and inhibits mTORC1, which blocks cytokine-driven T-cell proliferation and arrests the cycle at G1/S. The block is downstream: IL-2 is still produced, but the cell does not respond to it.
• Cyclosporin A → cyclophilin → calcineurin. Same target as tacrolimus, different immunophilin. Cyclosporin A is a cyclic peptide, not a macrolide, and does not touch FKBP12.

Cyclosporin A, for its part, is described in the pharmacological literature as effectively a prodrug that engages cyclophilin to form a complex that then engages calcineurin. Its inhibitory potency is lower than tacrolimus on a molar basis, which is one of the reasons tacrolimus has become the dominant calcineurin inhibitor in transplant practice.

The two mechanism groups also sit in different parts of a supplier catalogue. Both are filed under immunology and immunosuppressant actives, while the mTOR-facing molecules overlap with the wider signaling inhibitor and kinase inhibitor ranges, where ATP-competitive mTOR kinase inhibitors such as sapanisertib are catalogued alongside the allosteric rapalogs. The two mTOR inhibitor classes are not interchangeable: rapalogs bind FKBP12 and inhibit mTORC1 only, whereas ATP-competitive inhibitors occupy the kinase domain and inhibit both mTORC1 and mTORC2.

3. CAS Numbers, Molecular Formula & Identity Traps

Physicochemical values below are compiled from published literature and are indicative for comparison; they are not specification limits.

Identity traps in this family

• Everolimus is sirolimus plus one 2-hydroxyethyl group. C₅₃H₈₃NO₁₄ against C₅₁H₇₉NO₁₃; a difference of C₂H₄O. Because everolimus is made from sirolimus, the parent is a specified impurity in the derivative — residual sirolimus is a normal, controlled item on an everolimus specification, not a defect.
• Temsirolimus is a prodrug of sirolimus. The same relationship applies in reverse: sirolimus is the controlled related substance, and total exposure to the active species is a sirolimus exposure. A buyer comparing temsirolimus and sirolimus is comparing an ester and its parent, not two activities.
• Tacrolimus is traded in two hydrate states. Anhydrous tacrolimus (104987-11-3, ≈804.0 g/mol) and tacrolimus monohydrate (109581-93-3, ≈822.0 g/mol) differ by about 2.2% in molecular weight, which is precisely the order of magnitude of an assay discrepancy that a hydrate-state mismatch produces.
• Ridaforolimus and deforolimus are the same molecule. The names AP23573, deforolimus and ridaforolimus are used interchangeably across the literature for CAS 572924-54-0.
• Cyclosporin A is a cyclic peptide, not a macrolide. It is not a member of the same structural class as sirolimus and tacrolimus at all, despite being discussed in the same clinical context. Naming variants — cyclosporin, ciclosporin, cyclosporine — all refer to the same INN substance.
• Zotarolimus is also published as ABT-578. A catalogue entry under either name resolves to CAS 221877-54-9.

4. The Single Fermentation Root of the Rapalog Family

The four semi-synthetic rapalogs are not four independent manufacturing routes. They are four derivatisations of one fermentation product.

• Sirolimus is produced by fermentation of Streptomyces hygroscopicus, the organism originally isolated from a soil sample from Rapa Nui. At production scale the fermentation runs on the order of a week, is followed by solvent extraction of the broth, and is completed by preparative chromatographic purification of a 31-membered macrocyclic lactone.
• Everolimus, temsirolimus, zotarolimus and ridaforolimus are each made by modifying that fermentation product at the C-40 or C-42 position — an ether, an ester, a tetrazole and a phosphinate respectively.
• Tacrolimus comes from a different organism, Streptomyces tsukubaensis, and cyclosporin A from the fungus Tolypocladium inflatum. Neither shares fermenter capacity, strain bank or purification train with the sirolimus route.

It also explains an ordering pattern that looks odd from a commodity-chemical perspective: a buyer of a gram-scale reference quantity and a buyer of a multi-kilogram API campaign are served from the same purification train, so minimum order quantities in this family are set by the cost of occupying that train, not by the mass of the material.

5. Sirolimus (Rapamycin) — The Parent Molecule

CAS 53123-88-9 C₅₁H₇₉NO₁₃ MW 914.17 Fermentation natural product

Sirolimus is the reference point for the whole family: a natural macrolide lactone, first isolated as an antifungal from soil, subsequently developed as an immunosuppressant and approved for kidney transplant maintenance in 1999. Its melting range sits around 183–185 °C, but the compound degrades well before that, and its aqueous solubility is under 3 µg/mL, with a LogP above 4.

Where the volume comes from

• Transplant immunosuppression. Used in maintenance regimens, frequently in calcineurin-inhibitor-sparing protocols, where its non-nephrotoxic profile relative to the calcineurin inhibitors is the clinical rationale. Its principal non-immune toxicities — hyperlipidaemia, thrombocytopenia and impaired wound healing — differ from the calcineurin inhibitor profile, which is what makes the combination pharmacologically useful.
• Drug-eluting stent coating. First-generation coronary stents used sirolimus as the antiproliferative agent, establishing a device-bound demand channel that persists in the market alongside everolimus- and zotarolimus-eluting platforms.
• Lymphangioleiomyomatosis and other niche indications. A small but stable specialist prescription base.
• Research-grade demand — the channel that distinguishes this molecule from every other API on this site. Rapamycin is the most studied pharmacological intervention in mammalian lifespan and healthspan research, and the resulting non-pharma demand is large, persistent and insensitive to transplant pricing. It sits entirely outside the GMP API market and is a separate supply line.

Handling

Sirolimus is sensitive to light, moisture and elevated temperature, and is supplied as a micronised powder in moisture-protective packaging. Photostability and moisture protection are therefore part of the quality case for a sirolimus lot, not storage-house conveniences — a lot that has been held warm, damp or exposed to light is analytically different from the same lot held correctly, and both may meet the same assay on paper.

6. Everolimus — The 40-O-Hydroxyethyl Workhorse

CAS 159351-69-6 C₅₃H₈₃NO₁₄ MW 958.23 Semi-synthetic from sirolimus

Everolimus carries the broadest label in the rapalog family: transplant immunosuppression plus oncology indications spanning renal cell carcinoma, hormone-receptor-positive breast cancer, pancreatic neuroendocrine tumours and tuberous-sclerosis-complex-related lesions. It appears on the WHO Model List of Essential Medicines as a targeted antineoplastic therapy.

What matters to a buyer

• It is a derivative, so its impurity profile is inherited. Everolimus is manufactured by introducing a 2-hydroxyethyl ether at the 40-hydroxyl of sirolimus. Unreacted sirolimus and over-alkylated species are the characteristic impurities, and a supplier's ability to control them reflects the maturity of its purification step rather than its reactor capacity.
• Its pharmacokinetics differ from the parent in ways that matter. Oral bioavailability is around 20% against roughly 14% for sirolimus; protein binding is lower at approximately 74%; and the terminal half-life is shorter, at around 30 hours versus 55 hours. For a formulation developer, the shorter half-life and better solubility are the reason everolimus is easier to formulate than sirolimus.
• Fewer qualified suppliers than sirolimus, at a higher unit cost. The additional synthetic step, the need to control the parent as a specified impurity, and the oncology dossier requirements narrow the supplier field. Buyers in regulated markets should expect to see DMF or CEP status as a gating condition rather than a differentiator.
• Solid-dispersion dependence. Oral everolimus products rely on enabling formulation technology, so the API's particle-size distribution and solid-state form carry more weight in the specification than the certificate of analysis alone suggests.

7. Temsirolimus — The Water-Soluble Ester Prodrug

CAS 162635-04-3 C₅₆H₈₇NO₁₆ MW 1030.29 IV oncology only

Temsirolimus is a 42-ester of sirolimus, designed to be more soluble than the parent so that it can be given intravenously. It was approved in 2007 for advanced renal cell carcinoma and remains an intravenous, hospital-administered product.

• It is a prodrug, and the specification says so. After administration it is converted to sirolimus, and the pharmacological activity is largely attributable to that conversion. Temsirolimus therefore appears in the same analytical relationship to sirolimus as everolimus does, from the opposite direction.
• Its size is a consequence of its route. An IV-only oncology product addresses a narrower patient population than an oral transplant or oncology product, and the API demand reflects that. Temsirolimus is a kilogram-scale, campaign-produced material rather than a routine order line.
• Its molecular weight is the highest in the family at 1030.29 g/mol — worth noting on any potency conversion, because milligram-per-milligram comparisons across this family are not comparisons of molar exposure.

8. Zotarolimus — The Device-Only Rapalog

CAS 221877-54-9 C₅₂H₇₉N₅O₁₂ MW 966.21 Stent coating

Zotarolimus is a C-40 tetrazole derivative of sirolimus developed specifically as a stent-coating drug, and it has never been marketed as an oral or injectable medicine. Its commercial route is the drug-eluting coronary stent, through the Endeavor generation and then the Resolute and Resolute Onyx platforms.

• The buyer is a device manufacturer, not a generic pharma company. Zotarolimus API is purchased under device quality agreements, with device-oriented change control, biocompatibility and extractables/leachables expectations rather than tablet-dossier expectations. It does not circulate on the open generic API market.
• Order scale is small and fixed by device demand. Coating loads per stent are measured in micrograms, so even large stent volumes translate into modest API masses — which is exactly why this molecule is invisible in aggregate API trade statistics.

9. Ridaforolimus — Designed, Tested, Never Approved

CAS 572924-54-0 C₅₃H₈₄NO₁₄P MW 990.21 No commercial product

Ridaforolimus, also published as deforolimus and as AP23573, is a C-40 dimethylphosphinate derivative of sirolimus, developed jointly under an oncology programme and taken through late-stage trials in endometrial cancer, osteosarcoma and soft tissue sarcoma. It was not approved, and no commercial product exists.

• Its design intent is legible in its properties. At roughly 200 µg/mL it is by a wide margin the most water-soluble rapalog, and the phosphinate group is the reason. Its half-life of approximately 49 hours sits between sirolimus and everolimus.
• Its place in the trade is analytical, not commercial. Realistic enquiries are for reference standards, impurity standards and gram-scale research quantities. A purchase order for commercial-scale ridaforolimus API has no counterpart product to supply.
• It completes the design logic of the family. Each rapalog is an attempt to repair one property of sirolimus: everolimus shortens the half-life and improves solubility, temsirolimus adds water solubility for intravenous use, zotarolimus maximises lipophilicity for local delivery, ridaforolimus maximises aqueous solubility. Reading the four together is the fastest way to understand why the family exists at all.

10. Tacrolimus & Cyclosporin A — Adjacent, Not Interchangeable

These two are the calcineurin inhibitors, and both are frequently quoted in the same enquiry as the rapalogs. They are not members of the same mechanisic class and not substitutes for any rapalog.

Tacrolimus

• Origin and form. A macrolide lactone from Streptomyces tsukubaensis, discovered in 1987. Traded as anhydrous tacrolimus (CAS 104987-11-3, ≈804.0 g/mol) or as the monohydrate (CAS 109581-93-3, ≈822.0 g/mol). The European Pharmacopoeia monograph for tacrolimus monohydrate is monograph 2244.
• Pharmacopoeial assay basis. The monohydrate monograph sets content from 97.0% to 102.0% for the sum of tacrolimus, tacrolimus compound I and tacrolimus compound II, expressed on the anhydrous substance.
• Narrow therapeutic window. Tacrolimus requires therapeutic drug monitoring in transplant practice; the WHO Expert Committee specifically noted this when recommending its inclusion on the Model List, which it entered in 2021 on the complementary list.
• Routes and dose forms. Immediate-release capsules, once-daily modified-release, granules for oral suspension, intravenous concentrate, and a topical ointment used in atopic dermatitis. The topical route is a significant and growing API demand channel that has nothing to do with transplant medicine.
• Light sensitivity is written into the pharmacopoeia. The related-substances test for tacrolimus monohydrate is carried out protected from light, with test and reference solutions allowed to stand for three hours at room temperature before use — a direct measure of how light-sensitive this molecule is in solution.

Cyclosporin A

• Structure. An undecapeptide — eleven amino acids in a cyclic peptide backbone, C₆₂H₁₁₁N₁₁O₁₂, MW 1202.61 — produced by fermentation of Tolypocladium inflatum. It is the oldest of the molecules in this comparison and the most chemically different.
• Essential-medicine status. On the WHO Model List of Essential Medicines since 1991, under immunomodulators for non-malignant disease.
• The canonical formulation problem of the class. Cyclosporin A is practically insoluble in water, and the historical difference between the oil-based and the later microemulsion formulation is the standard example of formulation determining clinical exposure in immunosuppression. Any API-level discussion of cyclosporin A that ignores the formulation dimension is incomplete.
• Additional demand channels. Ophthalmic emulsion for dry eye disease and veterinary immunosuppression — both meaningfully larger in aggregate than the transplant channel in some markets.
• Mature and heavily genericised supply base. Multi-source, price-competitive, with well-established pharmacopoeial standards. It is the commodity anchor of this comparison.

11. Global Export Volume Ranking (China API Supply) ★

The decisive question in this category is which of these seven is really moving volume? The ranking below is a qualitative index based on relative cross-border API trade activity from Chinese and other Asian supply chains. It is a directional market view, not a published statistical series — but the ordering is stable and the gaps are large.

1. Tacrolimus (CAS 104987-11-3 / monohydrate 109581-93-3) — the volume leader of the whole group. Transplant maintenance demand plus a large topical atopic-dermatitis channel, essential-medicines status since 2021, and a broad multi-source generic base make this the highest-volume API in the comparison by a wide margin. The practical consequence is price compression and a supplier field large enough that documentation status, not availability, decides the award. Anhydrous and monohydrate grades are both in circulation, and the hydrate state belongs in the specification rather than in correspondence.
2. Cyclosporin A (CAS 59865-13-3) — the mature bulk line. Essential-medicines status since 1991, a heavily genericised transplant market, plus ophthalmic emulsion and veterinary channels that add demand well beyond transplantation. Volume is high and stable but structurally mature, with price set by multi-source competition. Its cyclic-peptide structure means a completely different impurity universe and analytical toolset from the macrolides.
3. Sirolimus (CAS 53123-88-9) — the largest rapalog by volume, and the most unusual demand mix. Transplant maintenance, stent coating and lymphangioleiomyomatosis provide the pharma base; on top of that sits a large research-grade channel driven by longevity research, which is insensitive to transplant pricing and sustains demand at a level no other rapalog approaches. Unit price is the highest among the clinically used rapalogs, and the grade separation between GMP API and research-grade material is a hard boundary in this molecule.
4. Everolimus (CAS 159351-69-6) — premium volume, narrow supplier field. Oncology and transplant demand together place it second among the true rapalogs. The additional semi-synthetic step, the requirement to control sirolimus as a specified impurity, and oncology dossier requirements keep the qualified supplier count low, which supports price. Growth is tied to generic entry in oncology rather than to transplant.
5. Temsirolimus (CAS 162635-04-3) — small, IV-bound, stable. Intravenous administration restricts the addressable population and caps API volume well below every oral molecule in the comparison. Orders are kilogram-scale and campaign-scheduled. Its commercial value to a supplier lies in the oncology dossier and the certification package rather than in mass.
6. Zotarolimus (CAS 221877-54-9) — invisible in the open API market by construction. Supply is bound to coronary stent programmes through device quality agreements. Coating loads are measured in micrograms per device, so even substantial stent volumes translate into modest API mass. This molecule should never be forecast through generic-API volume logic.
7. Ridaforolimus (CAS 572924-54-0) — no commercial volume. Late-stage trials in sarcoma and endometrial cancer were completed without approval, so there is no product to supply. Realistic demand is confined to reference standards, impurity standards and gram-scale research quantities.

12. Solubility, Bioavailability & Formulation Reality

Every rapalog in clinical use is practically insoluble in water. That single physicochemical fact shapes the entire product-development landscape of the family.

Tacrolimus adds a second dimension. Because it has a narrow therapeutic window and requires therapeutic drug monitoring in transplant practice, its modified-release and immediate-release forms are not automatically interchangeable, and the granule and capsule forms have distinct dissolution expectations in the destination market.

13. Manufacturing Difficulty, Potency & Storage

Why this family is hard to make

• Fermentation plus semi-synthesis. Sirolimus requires a multi-day fermentation of Streptomyces hygroscopicus, solvent extraction and preparative chromatographic purification of a 31-membered macrocyclic lactone. Tacrolimus and cyclosporin A require separate fermentation routes with different organisms and different down-stream trains.
• Stereochemical density. These molecules carry multiple defined stereocentres and several double-bond geometries; the impurity profile is dominated by closely related stereoisomers and derivatives rather than by gross chemical degradation, which puts the analytical burden on chromatographic resolution.
• Light and moisture sensitivity throughout. Handling, packaging and analytical method conditions are constrained by photolability in this family — the pharmacopoeial related-substances test for tacrolimus monohydrate is itself carried out protected from light.

Potency and containment

• Therapeutic doses in this family are small — single-digit milligrams per day, and micrograms per dose by the topical route — which places the compounds in high-potency handling territory with containment, dust control and industrial-hygiene monitoring requirements.
• Tacrolimus carries the additional constraint of a narrow therapeutic window, which propagates into manufacturing as tight content-uniformity and assay expectations rather than as a pure safety matter.

14. Pharmacopoeia, HS Classification & Export Documentation

Pharmacopoeial standards

• Tacrolimus monohydrate has a European Pharmacopoeia monograph (monograph 2244), with content specified as 97.0–102.0% for the sum of tacrolimus and its compounds I and II, expressed on the anhydrous substance, and with a related-substances test performed under light protection.
• Reference standards are catalogued by the major pharmacopoeial bodies for the principal molecules, including tacrolimus and sirolimus. Where a pharmacopoeial monograph does not exist for a specific rapalog, the controlling specification is the sponsor's DMF together with an in-house reference standard — and that distinction should be visible in the documentation package.
• Fermentation-derived status brings its own documentation expectations: the identity of the fermentation organism, control of the fermentation medium, residual solvent and elemental impurity data, and a statement on the absence of cross-contamination from other antibiotic fermentations on the same site.

Customs classification

Classification in this family is decided per molecule, not per therapeutic class, and the practical answer is not the intuitive one.

• Heading HS 2941 (antibiotics) is the correct home for these bulk organic APIs, most commonly under 2941.90 ("other").
• The macrolide subheading 2941.50 is not the correct home. That subheading is written for erythromycin and its derivatives, and applying it to a sirolimus or tacrolimus shipment because the molecule is chemically a macrolide is a common and avoidable classification error.
• US practice: US Customs classified bulk sirolimus under HTSUS 2941.90.1050 in ruling N089882, at a free rate of duty.
• Chinese practice: sirolimus and cyclosporin are declared under 29419090. Tacrolimus appears under both 2941.90 and 2934.99 across national schedules, so a shipment record showing tacrolimus under a heterocyclic heading is not evidence of a different substance.
• Finished medicaments move to Chapter 30 (3003/3004); a zotarolimus-eluting stent is neither an API nor a medicament but a device, and does not follow API classification logic at all.
• Additional national measures can apply on top of the general rate. For example, US Section 301 additional tariffs are applied to specified Chinese-origin chemical goods. The applicable rate depends on the specific product category and the current measure list, and it is confirmed with a customs broker on a per-shipment basis rather than assumed to equal the general rate.

Regulatory position

Documentation package

15. API Selection Guide for Formulation Projects

Seven criteria generally decide the selection in this family, in the order below.

1. Is the target mTORC1 or calcineurin? This is the first question, and it eliminates half the list immediately. mTORC1 points to a rapalog; calcineurin points to tacrolimus or cyclosporin A.
2. What is the required route of administration? Oral development points to sirolimus, everolimus, tacrolimus or cyclosporin A. Intravenous oncology points to temsirolimus. A device coating points to zotarolimus or sirolimus. Research reference work points to ridaforolimus.
3. Is the project a volume play or a differentiation play? Tacrolimus and cyclosporin A are the volume plays with multi-source supply and price competition. Everolimus and sirolimus are the differentiation plays among the rapalogs, with narrower supplier fields and higher unit cost.
4. Which hydrate, ester or salt state is specified? Tacrolimus projects must declare monohydrate or anhydrous. Prodrug projects must declare the parent as a specified impurity. The specification is where this is settled, and it is not recoverable downstream.
5. Which regulatory filings will the dossier cite? The supplier's DMF or CEP status in the destination market matters here, together with confirmation that the filed specification matches the grade in question.
6. Is device-bound supply involved? Zotarolimus procurement runs through device quality agreements with device change control, not through generic API order logic.
7. Is the grade boundary understood? For sirolimus, the distinction between GMP API and research-grade material is a hard line, and the documentation that travels with the lot is what establishes which side of it the material sits on.

Projects that fall outside this family but follow the same sourcing logic are covered in the sibling category comparisons, including the prostaglandin analogs API comparison, which applies the same target-first, parent-molecule-second framework to a different receptor family. Cyclosporin A is also carried as a standalone product entry at cyclosporin A, CAS 59865-13-3.

16. Frequently Asked Questions

17. Conclusion

Three practical rules apply across the family. First, the target decides the category — sirolimus and tacrolimus share a binding protein but not a mechanism, and a quotation written for one is not valid for the other. Second, the parent molecule decides the supply chain — four of the five rapalogs are semi-synthetic derivatives of fermentation-derived sirolimus, so their availability, lead time and price move together. Third, the specification decides the outcome — hydrate state, ester state, residual parent content and particle size are functional attributes in this family, not documentation formalities.

On volume, the honest answer is counter-intuitive: the two calcineurin inhibitors that buyers quote alongside the rapalogs move more API than all five rapalogs combined, and the molecule that names the family's mechanism is not its volume leader. Sirolimus remains the largest and most strategically interesting rapalog, principally because its demand mix includes a research-grade channel with no equivalent elsewhere in the API catalogue. Zotarolimus and ridaforolimus, meanwhile, should be planned through device supply chains and reference-standard sourcing respectively — not through generic-API volume logic.