1. Orlistat (CAS 96829-58-2): An Overview
Orlistat (CAS 96829-58-2) is a semi-synthetic active pharmaceutical ingredient (API) that acts as a potent inhibitor of gastrointestinal lipases. Chemically it is the hydrogenated derivative of the natural product lipstatin, a metabolite produced by the actinomycete Streptomyces toxytricini. Because the molecule is obtained by fermenting lipstatin and then saturating a double bond by catalytic hydrogenation, Orlistat is properly described as a semi-synthetic fermentation-derived API rather than a purely synthetic small molecule.
Orlistat is a white to quasi-white crystalline powder with the molecular formula C29H53NO5 and a molecular weight of 495.7 g/mol. Its defining structural feature is a strained four-membered beta-lactone (oxetan-2-one) ring, linked through an ester bond to an N-formyl-L-leucine residue and carrying a long aliphatic chain. This combination of a reactive beta-lactone warhead with a lipophilic tail allows the molecule to bind the catalytic site of gastric and pancreatic lipases and block the hydrolysis of dietary triglycerides.
This article reviews the chemistry, manufacturing route, impurity profile, specifications and applications of Orlistat from the perspective of a supplier and process engineer. It is written for formulators, quality-control scientists, sourcing teams and researchers who need a reliable technical reference for the material, its grades and its handling.
2. Chemical Identity and Physicochemical Properties
Orlistat belongs to the lipstatin family of lipase inhibitors. Its identity, as defined by the pharmacopoeial monographs and the substance registry, is summarized below.
| Property | Value |
|---|---|
| Chemical name (IUPAC) | [(2S)-1-[(2S,3S)-3-Hexyl-4-oxooxetan-2-yl]tridecan-2-yl] (2S)-2-formamido-4-methylpentanoate |
| Common / INN name | Orlistat (tetrahydrolipstatin, THL) |
| CAS Registry Number | 96829-58-2 |
| Molecular formula | C29H53NO5 |
| Molecular weight | 495.7 g/mol |
| Appearance | White or quasi-white crystalline powder |
| Solubility | Practically insoluble in water; soluble in ethanol and chloroform |
| Optical rotation | -48° to -51° (20°C, 30 mg/mL in dehydrated alcohol) |
| Stereocentres | Four (three contiguous in the beta-lactone/ester region plus the leucine alpha-carbon) |
| Functional groups | Beta-lactone (oxetanone), ester, secondary formamide, long alkyl chain |
| PubChem CID | 3034010 |
The low aqueous solubility of Orlistat is a defining property for formulation work. Since the compound is practically insoluble in water, oral solid dosage forms rely on particle-size reduction, granulation or lipid-based dispersion strategies to present the API to the gastrointestinal tract in a usable form. For the bulk API itself, solubility behaviour also affects the choice of crystallization, filtration and drying steps during manufacture.
The isomeric SMILES notation of the molecule is:
CCCCCCCCCCC[C@@H](C[C@H]1[C@@H](C(=O)O1)CCCCCC)OC(=O)[C@H](CC(C)C)NC=O
The CCCCCC segment flanking the lactone ring and the long tridecanyl backbone supply the lipophilic character required for interaction with the enzyme’s lipid-binding channel, while the N-formyl-L-leucine ester provides the recognition element. The stereochemistry is not incidental: the biological activity of Orlistat depends on the correct configuration at all four stereocentres.
3. Mechanism of Action: Covalent Inhibition of Gastrointestinal Lipases
Dietary fat is ingested mainly as triglycerides, which must be hydrolysed to free fatty acids and monoglycerides before they can be absorbed across the intestinal wall. Two enzymes carry out most of this hydrolysis: gastric lipase, which begins the process in the stomach, and pancreatic lipase, which completes it in the small intestine with the help of colipase.
Orlistat acts as a covalent inhibitor of these enzymes. The beta-lactone carbonyl is highly electrophilic because of the ring strain of the four-membered oxetanone, and it is attacked by the nucleophilic serine residue (Ser152 in human pancreatic lipase) that forms part of the enzyme’s catalytic triad. The result is an acyl-enzyme intermediate in which the opened lactone ring is esterified to the active-site serine. This acyl-enzyme is formed rapidly and hydrolyses only very slowly, so the enzyme is effectively inactivated and cannot process further triglyceride molecules.
Because Orlistat works at the catalytic site within the gut lumen, the inhibition is local rather than systemic. The molecule is only minimally absorbed from the gastrointestinal tract, so its activity is largely confined to the surface of the intestine. Under typical therapeutic regimens, the resulting reduction in fat digestion corresponds to roughly 30% of dietary fat, as reported in the product labelling. The undigested fat is not absorbed and is excreted, which reduces the net energy available from a meal.
The same beta-lactone reactivity that makes Orlistat an effective inhibitor also explains why the molecule must be handled with attention to stability. Water, nucleophiles and heat can open the lactone ring and generate the “open-ring” impurities that are controlled in the finished API.
4. Manufacturing Route: Semi-Synthesis from Lipstatin Fermentation
The commercial route to Orlistat is a two-stage process: a fermentation stage that produces the natural product lipstatin, followed by a chemical hydrogenation stage that converts lipstatin into Orlistat. This hybrid route is the basis for the industrial supply of the API.
Stage 1 – Fermentation of lipstatin
Lipstatin is produced by fermentation of a selected Streptomyces toxytricini strain. The culture is grown in a nutrient medium containing carbon and nitrogen sources, and the lipstatin titre is influenced by the supply of fatty-acid precursors and by process parameters such as aeration, agitation and temperature. Because lipstatin is a secondary metabolite, the fermentation is typically run with a defined feed profile and harvested at the point of maximum accumulation before degradation and by-product formation dominate.
Stage 2 – Recovery and purification of lipstatin
After harvest, the biomass is separated and lipstatin is recovered from the broth and the mycelium by solvent extraction. The crude extract is then concentrated and purified – typically by a combination of solvent partitioning, adsorption or chromatography and crystallization – to give a lipstatin intermediate of sufficient purity for hydrogenation.
Stage 3 – Catalytic hydrogenation to Orlistat
Lipstatin contains a carbon-carbon double bond adjacent to the lactone ring. Catalytic hydrogenation – classically over a palladium-on-carbon catalyst under controlled hydrogen pressure – saturates this bond to give the tetrahydro derivative, which is Orlistat. The hydrogenation must be controlled carefully to avoid over-reduction, to preserve the sensitive beta-lactone ring and to keep the stereochemistry intact. The choice of catalyst, solvent, temperature and hydrogen pressure all influence both conversion and the level of hydrogenation-related impurities.
Stage 4 – Isolation and finishing
The hydrogenated product is isolated, recrystallized and dried to give the API as a white to quasi-white crystalline powder. Purification steps are designed to remove lipstatin-related impurities, open-ring degradation products and residual solvents, and to bring the optical rotation and related-substance profile within pharmacopoeial limits.
Because the route depends on a fermentation intermediate, the economics of Orlistat are driven by fermentation yield and by the efficiency of the downstream purification, not by the cost of the final hydrogenation alone. This is why only a limited number of manufacturers worldwide are able to supply the material at commercial scale.
5. Comparison of Manufacturing Approaches
Although the fermentation/hydrogenation route dominates commercial production, several approaches to the molecule exist in the literature and in development. They differ in raw-material basis, cost structure and the impurities they generate.
| Route | Starting material | Key steps | Advantages | Limitations |
|---|---|---|---|---|
| Fermentation + hydrogenation (commercial) | S. toxytricini culture; lipstatin | Fermentation, extraction, purification, catalytic hydrogenation, crystallization | High stereochemical fidelity; matches the natural configuration; scalable to tonnes | Depends on fermentation titre; complex downstream purification; capital-intensive |
| Total synthesis (research scale) | Simple chiral building blocks | Multi-step asymmetric synthesis of the beta-lactone, esterification with N-formyl-L-leucine | Independent of fermentation; allows analogue work | Long, costly; difficult to scale; stereochemical control demanding |
| Chemo-enzymatic / biocatalytic | Synthetic or semi-synthetic intermediates | Enzymatic resolution or desymmetrization combined with synthesis | Potentially high enantioselectivity; milder conditions | Enzyme availability and cost; limited industrial precedent |
For the formulator and buyer, the practical consequence is that essentially all commercial Orlistat originates from the fermentation/hydrogenation sequence. Understanding that origin helps when interpreting impurity profiles, because the characteristic impurities reflect the lipstatin route and the sensitivity of the beta-lactone ring.
6. Stereochemistry and Chiral Quality
Orlistat contains four stereocentres, and its activity is stereospecific: the all-(S) configuration of the lactone ring, the tridecanyl ester and the leucine residue is required for efficient lipase inhibition. A change at any of these centres can reduce potency and is treated as an impurity rather than as an interchangeable form.
Because the molecule is produced through fermentation, the natural configuration of lipstatin already provides the correct stereochemistry for the key centres, and hydrogenation preserves it. This is a major advantage compared with a total synthesis, where each stereocentre would have to be set deliberately. The chiral purity of the finished material is nevertheless monitored, because process stress, storage or incomplete reaction can generate stereochemical impurities such as D-leucine orlistat and open-ring epimers.
Optical rotation is a simple but informative release test for chiral quality. For Orlistat, the specification typically requires a specific rotation in the range of -48° to -51° measured at 20°C with a 30 mg/mL solution in dehydrated alcohol. A result outside this window signals a stereochemical or purity problem and triggers further investigation by chiral chromatography.
7. Impurity Profile and Quality Control
The impurity profile of Orlistat is defined by both its fermentation origin and the reactivity of its beta-lactone ring. Pharmacopoeial monographs and customer specifications control a set of named related substances together with limits on individual and total unknowns.
| Impurity | Likely origin | Typical limit |
|---|---|---|
| Orlistat Related Compound A | Process-related; hydrogenation or purification by-product | NMT 0.2% |
| Orlistat Related Compound B | Process-related related substance | NMT 0.05% |
| Orlistat Related Compound C | Process-related related substance | NMT 0.05% |
| Orlistat Related Compound D | Process-related related substance | NMT 0.2% |
| N-Formyl-L-leucine | Hydrolysis fragment of the ester bond | NMT 0.2% |
| Orlistat open ring epimer | Lactone ring opening with stereochemical change | NMT 0.2% |
| D-Leucine orlistat | Stereochemical impurity at the leucine centre | NMT 0.2% |
| Orlistat open ring amide | Ring-opened degradation product | NMT 0.1% |
| Individual unidentified impurity | Various | NMT 0.1% |
| Total impurities | Combined | NMT 1.0% |
Release testing for Orlistat combines chromatographic and classical methods. Reverse-phase HPLC with UV detection is used to quantify the related substances and to confirm the assay; chiral HPLC or an equivalent technique is used where stereochemical purity must be demonstrated; optical rotation provides a rapid check of overall chiral quality; and Karl Fischer titration is used to determine residual water. Residue on ignition and appearance round out the pharmacopoeial test set.
Two impurities deserve particular attention from a stability standpoint. The open-ring epimer and the open-ring amide both arise from opening of the strained beta-lactone, so they tend to increase when the material is exposed to moisture or heat over time. Controlling water content and storage conditions is therefore directly linked to keeping the impurity profile within specification over the shelf life of the material.
8. Specifications and Pharmaceutical Grades
Orlistat is supplied against the USP and EP monographs, and PolyBlueChem provides the material as a white to quasi-white crystalline powder with the release specifications summarized below.
| Parameter | Specification |
|---|---|
| Appearance | White or quasi-white crystalline powder |
| Optical rotation | -48° to -51° (20°C, 30 mg/mL in dehydrated alcohol) |
| Assay (anhydrous, solvent-free basis) | 98.0% – 101.5% |
| Residue on ignition | NMT 0.1% |
| Residual water | NMT 0.2% |
| Related substances | Per monograph and lot COA (individual and total limits) |
| Grade | Typical use | Key requirements |
|---|---|---|
| USP grade | United States pharmacopoeial compliance; formulation and QC reference | Conforms to USP Orlistat monograph; full COA |
| EP grade | European pharmacopoeial compliance; formulation and QC reference | Conforms to EP Orlistat monograph; full COA |
| Reference / research grade | Analytical reference standards, method development, research | Documented purity and identity; lot-specific data |
The assay range of 98.0% to 101.5% on the anhydrous, solvent-free basis, together with a total-impurities limit of 1.0% and tight related-substance limits, defines an API of high and reproducible quality. Buyers should confirm that the COA reports assay on the correct basis, since residual water and residual solvents must be excluded before the assay is compared with specification.
9. Applications in Pharmaceutical Formulation
The principal application of Orlistat is as the active ingredient of oral pharmaceutical products that reduce the absorption of dietary fat through gastrointestinal lipase inhibition. Its very low water solubility makes formulation work a central part of product development.
- Oral solid dosage forms. Orlistat is formulated into orally administered products where the API is presented to the gut lumen to act on lipases. Because the compound is practically insoluble in water, particle-size reduction and granulation are used to improve content uniformity and to control dissolution behaviour.
- Micronized and granulated API. Reducing particle size increases the surface area available for interaction with the enzyme, and it also helps achieve blend uniformity at the low drug loads typical of these products.
- Impurity and reference-standard work. Because the impurity profile is rich and pharmaceutically significant, Orlistat and its related compounds are used as reference materials in analytical method development and quality control.
- Delivery research. As a classic example of a poorly water-soluble active, Orlistat is studied in formulation research on solid dispersion, lipid-based and other enabling technologies.
| Application | Form | Key API requirement |
|---|---|---|
| Oral lipase-inhibitor product | Capsule / granule | Assay, particle size, low water, controlled impurities |
| Analytical reference standard | Neat material | Documented identity, assay, chiral purity |
| Formulation research | Various | Well-characterized lot with full COA |
10. Beyond Weight Management: Research and Adjacent Uses
Although Orlistat is best known as a lipase inhibitor, the same beta-lactone chemistry that gives it high potency against human lipases makes it a valuable tool in several research settings. Orlistat is widely used as a positive control and reference inhibitor in lipase assays, and it has been studied in the literature for its activity against other enzymes and organisms that carry serine hydrolases or related targets.
Reported areas of academic and industrial interest include the use of Orlistat as a chemical-biology probe for studying lipid metabolism, its investigation in anti-parasitic and anti-infective research, and the study of its beta-lactone pharmacophore in drug discovery. These are research-stage applications: they do not change the material’s identity or its specification, but they explain the steady demand for high-purity Orlistat from laboratories as well as from finished-dosage manufacturers.
For sourcing purposes, research customers typically need small quantities of well-characterized material with a complete analytical package, whereas formulation customers need commercial-scale quantities with a consistent COA and, where relevant, regulatory support. Both are served by the same USP/EP-quality API.
11. Downstream Products and Dosage Forms
The material supplied as Orlistat API moves downstream into a limited but well-defined set of products. Understanding these flows helps suppliers and buyers align on grade, documentation and volume.
- Oral pharmaceutical products that use gastrointestinal lipase inhibition as their mechanism of action. These are the largest consumers of the API and require USP/EP-quality material with a full regulatory package.
- Analytical and reference materials supplied to QC laboratories and contract testing organizations, often in gram quantities.
- Research and development use in academic and industrial laboratories, from method development to chemical-biology studies.
Because the downstream product set is narrower than for a general industrial chemical, supply is dominated by a small group of qualified manufacturers. Buyers therefore benefit from confirming a supplier’s ability to provide consistent lots, complete documentation and reliable lead times rather than from chasing the lowest unit price alone.
12. Procurement: Packaging, MOQ, Documentation and Regulatory
Sourcing a fermentation-derived API such as Orlistat involves several considerations beyond the headline assay figure. The table below summarizes the points that experienced buyers check before placing an order.
| Consideration | What to confirm |
|---|---|
| Grade | USP or EP compliance, stated on the COA |
| Assay basis | Reported on the anhydrous, solvent-free basis (98.0% – 101.5%) |
| Impurity profile | All named related substances and total impurities within limits |
| Chiral quality | Optical rotation within -48° to -51° and chiral chromatography where required |
| Water content | NMT 0.2%, since water promotes beta-lactone ring opening |
| Packaging | Double-lined fiber drums (e.g., 1 kg / 5 kg / 25 kg), light- and moisture-protected |
| Documentation | COA, MSDS, and, on request, additional regulatory or quality documents |
| Storage and shelf life | Cool, dry, light-protected storage; retest period per COA |
Quality documentation is central to API procurement. A complete Certificate of Analysis should report appearance, identity, optical rotation, assay, water, residue on ignition and the related-substances results against the applicable monograph. Because Orlistat is a semi-synthetic, fermentation-derived ingredient, batch-to-batch consistency and a stable impurity profile matter as much as a single high assay value.
For customers working toward regulated markets, the origin, manufacturing history and quality-management system of the API matter, and additional documentation may be requested during qualification. Buyers are encouraged to discuss their specific regulatory and documentation needs with the supplier early in the sourcing process.
13. Storage, Handling and Safety
Orlistat should be stored in tight, light-resistant containers at controlled room temperature (below 25°C) and protected from moisture. The sensitivity of the beta-lactone ring to hydrolysis means that water content and storage conditions are directly linked to the stability of the material, and lots should be retested according to the retest period stated on the COA.
When handling the powder, standard good-manufacturing-practice precautions for potent pharmaceutical actives apply: use appropriate personal protective equipment, work in a well-ventilated area, avoid generating dust and prevent contact with skin and eyes. The material is intended for pharmaceutical and research use by qualified organizations; it should be handled only by trained personnel and stored securely, away from incompatible materials and out of reach of the general public.
As with any active ingredient, the safety data sheet (SDS) should be consulted for detailed hazard, first-aid, transport and disposal information, and local regulations governing the handling of pharmaceutical actives should be observed.
14. Frequently Asked Questions
What is Orlistat and what is it used for?
Orlistat (CAS 96829-58-2) is a semi-synthetic lipase inhibitor supplied as a pharmaceutical API. It is used as the active ingredient of oral products that reduce the absorption of dietary fat by inhibiting gastrointestinal lipases, and as a reference material in analytical and research work.
Is Orlistat natural or synthetic?
It is semi-synthetic. The natural product lipstatin is produced by fermentation of Streptomyces toxytricini and is then converted into Orlistat by catalytic hydrogenation, so the final API has both a fermentation and a chemical origin.
What is the molecular formula and molecular weight of Orlistat?
Orlistat has the molecular formula C29H53NO5 and a molecular weight of 495.7 g/mol. Its PubChem CID is 3034010.
What purity and assay does the supplied material meet?
The API is supplied at an assay of 98.0% to 101.5% on the anhydrous, solvent-free basis, with total impurities of not more than 1.0% and individual named related substances within the limits given in the COA and the applicable USP or EP monograph.
Why is optical rotation specified for Orlistat?
Optical rotation is a simple indicator of chiral quality. Orlistat activity depends on the correct configuration at its stereocentres, and the specification of -48° to -51° (20°C, 30 mg/mL in dehydrated alcohol) confirms that the material has the expected stereochemistry.
Why is water content important for Orlistat?
The beta-lactone ring in Orlistat can open in the presence of water, generating open-ring epimer and open-ring amide impurities. Keeping residual water at or below 0.2% and storing the material dry helps preserve the impurity profile over time.
How is Orlistat manufactured?
Commercially it is made by fermenting lipstatin, recovering and purifying the intermediate, and then hydrogenating it to saturate the double bond and give Orlistat, followed by crystallization and drying to the finished API.
How should Orlistat be stored and packaged?
Store below 25°C in tight, light-resistant containers protected from moisture. It is typically supplied in double-lined fiber drums of 1 kg, 5 kg or 25 kg; the retest period and storage conditions are stated on the COA.
What documentation is provided with each lot?
Each lot is supplied with a Certificate of Analysis covering appearance, identity, optical rotation, assay, water, residue on ignition and the related-substances profile. Additional quality or regulatory documentation can be provided on request.
Can Orlistat be supplied in research quantities as well as bulk?
Yes. The same USP/EP-quality API is supplied both in gram-scale quantities for laboratory and reference-standard use and in commercial-scale drums for formulation customers; packaging and documentation can be adapted to the application.
15. References and Further Reading
- United States Pharmacopeia (USP) monograph for Orlistat.
- European Pharmacopoeia (EP) monograph for Orlistat.
- PubChem Compound Summary, Orlistat, CID 3034010 (National Library of Medicine).
- Manufacturer product labelling for Orlistat, including the mechanism of action and the reported extent of dietary-fat inhibition.
Disclaimer: This article is provided for informational and technical reference purposes only. It does not constitute medical, prescribing, legal or regulatory advice, and it does not describe indications, doses or clinical use of any finished pharmaceutical product. Orlistat is an active pharmaceutical ingredient intended for use by qualified pharmaceutical and research organizations; handling and use are subject to applicable law and to the material’s safety data sheet.
PolyBlueChem supplies Orlistat (CAS 96829-58-2) as a USP/EP-grade API with a complete Certificate of Analysis. If you need specifications, a quotation or additional documentation for your application, contact our team. See also our guides to the Orlistat manufacturing process and how to buy Orlistat.