| HS Code | 613902 |
| Chemical Name | Mannitol |
| Molecular Formula | C6H14O6 |
| Molar Mass | 182.172 g/mol |
| Cas Number | 69-65-8 |
| Appearance | White crystalline powder |
| Odor | Odorless |
| Taste | Sweet, approximately 0.5–0.7 times sucrose |
| Density | 1.49 g/cm³ at 20 °C |
| Melting Point | 166–168 °C |
| Boiling Point | Decomposes before boiling |
| Water Solubility | 1 g dissolves in about 5.5 mL water at 20 °C |
| Solubility In Ethanol | Slightly soluble |
| Solubility In Ether | Insoluble |
| Hygroscopicity | Non-hygroscopic |
As an accredited Mannitol factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Mannitol, white crystalline powder, packaged in 25 kg polyethylene-lined fiber drums for safe handling and storage. |
| Container Loading (20′ FCL) | Mannitol packed in 20′ FCL, loaded in palletized bags/drums, secured and ventilated to prevent moisture damage. |
| Shipping | Mannitol is shipped as a white crystalline powder in sealed, food-grade bags or fiber drums, preferably in clean, dry containers. It requires protection from moisture, humidity, and extreme heat, with adequate ventilation. Non-hazardous under normal transport conditions; standard handling and good hygiene practices are recommended throughout logistics. |
| Storage | Store mannitol in a well-closed, tightly sealed container to protect it from moisture and contamination. Keep in a cool, dry, well-ventilated area away from direct sunlight, heat sources, and incompatible substances. Avoid prolonged exposure to high humidity, as mannitol can absorb moisture. Ensure area is clean and clearly labeled. |
| Shelf Life | Shelf life: typically 5 years when stored in a tightly sealed container in a cool, dry, well-ventilated area away from moisture. |
In direct compression of orally disintegrating tablets and chewable dosage forms, mannitol is specified as a non-hygroscopic filler-binder with low sensory sweetness and negligible reactivity toward amine-containing actives. Spray-dried direct-compression grades are commonly supplied with a laser-diffraction d50 of 110–160 µm per USP <429>, a bulk density of 0.45–0.55 g/mL, and a tapped density of 0.55–0.65 g/mL; the resulting compressibility is sufficient for high-speed rotary tablet presses operating at 40–80 rpm without pre-granulation. Formulation loading ranges from 60–90 wt% mannitol, with crospovidone at 2–5 wt% as a wicking disintegrant and magnesium stearate limited to 0.5–1.0 wt% because higher lubricant levels above 1.5 wt% reduce tablet tensile strength through hydrophobic particle coating. Compression on 10 mm flat-faced bevel-edge tooling at 8–18 kN produces tablet hardness values of 60–120 N and friability below 0.8% when tested according to USP <1216>. Orally disintegrating formulations typically meet disintegration times below 60 s in USP <701> and content uniformity acceptance limits under USP <905>. Mannitol grade selection directly affects punch sticking: β-mannitol exhibits brittle fracture and plastic deformation, whereas traces of α-mannitol or unconverted sorbitol can raise cohesion and require lubrication adjustment. Loss on drying should remain below 0.5% by USP <731>, and reducing sugars must not exceed 0.3% to avoid Maillard discoloration in formulations containing primary amine APIs. In low-shear V-blender operations, magnesium stearate is introduced as the final excipient and blended for 3–5 min at 20–25 rpm; over-blending reduces disintegration time but sacrifices compact hardness, a process conflict resolved by moving lubricant addition to a separate external lubrication station on the tablet press.
| Parameter | Standard / Method | Typical limit or range |
|---|---|---|
| Identification | USP-NF Mannitol monograph, IR absorption | Matches reference spectrum |
| Loss on drying | USP <731> | ≤0.5% |
| Residue on ignition | USP <281> | ≤0.1% |
| Reducing sugars | USP-NF Mannitol monograph | ≤0.3% |
| Particle size d50, spray-dried grade | Laser diffraction, USP <429> | 110–160 µm |
| Tablet disintegration, ODT | USP <701> | <60 s |
During lyophilization of heat-labile biologics and vaccine antigens, mannitol is added as a crystalline bulking agent at 2–10% w/v before sterile filtration through 0.22 µm PVDF or PES membranes. The freezing program is designed to avoid incomplete crystallization, because residual amorphous mannitol lowers the observed collapse temperature and produces shrunken or collapsed cakes. Amorphous mannitol has a reported glass transition temperature of the maximally freeze-concentrated phase between -33 °C and -28 °C when measured by modulated differential scanning calorimetry according to ISO 11357-2; annealing at -15 °C to -20 °C for 2–4 h promotes crystallization of the bulking agent before primary drying. Primary drying is conducted at a shelf temperature of -30 °C to -10 °C and chamber pressure of 50–150 mTorr for 24–48 h depending on fill depth; secondary drying is then ramped to 25–40 °C and held for 6–12 h. Residual moisture by Karl Fischer titration under USP <921> is controlled to 0.2–1.0% w/w, because drier cakes become electrostatically charged and friable, while wetter cakes risk loss of antigen secondary structure. Cake appearance and polymorphic state are monitored by X-ray powder diffraction per USP <941>; δ-mannitol and β-mannitol ratios vary with nucleation rate, and uncontrolled nucleation across different freeze-dryer shelves is a recognized scale-up failure that can shift reconstitution time from under 30 s to over 120 s in a 10 mL tubing vial filled with 5 mL of solution. Mannitol-sucrose-glycine ternary systems require balancing cryoprotection against crystallinity: high mannitol ratios above 4:1 mannitol-to-sucrose favor mechanical cake strength, whereas higher sucrose content depresses collapse temperature and necessitates lower primary drying shelf temperature. Controlled nucleation technology reduces batch-to-batch polymorphic variance by standardizing ice nucleation across shelves, but published data on mannitol-specific crystal size distribution under each controlled nucleation setting is limited.
The osmotic diuretic formulation is prepared by dissolving mannitol 20% w/v in Water for Injection at 60–70 °C, followed by cooling, pH adjustment to 4.5–7.0, and filtration through 0.22 µm membranes prior to terminal steam sterilization at 121 °C for 15 min. The calculated osmolality of the finished solution is approximately 1098 mOsmol/L, and the product is tested for particulate matter according to USP <788>, bacterial endotoxins by USP <85>, and sterility by USP <71>. The main process constraint is solubility at lower storage temperatures: 20% w/v mannitol is close to its saturation limit, and crystallization is accelerated when the infusion bag or vial is stored below 20 °C. If crystals appear, compendial labeling practice requires warming the sealed container to 70 °C with agitation, then cooling to 37 °C before intravenous administration to avoid vascular injury. Because residual microcrystals are a patient-safety risk, administration sets for mannitol infusion incorporate an in-line filter with nominal pore size of 5–15 µm. Intravenous dosing is typically calculated at 0.25–2 g/kg body weight depending on the clinical indication; intracranial pressure reduction protocols commonly administer 1.5–2 g/kg as an initial loading dose over 30–60 min. The finished product is not compatible with all container materials: mannitol solutions are preferentially filled into glass vials or polyolefin bags, and mixing with blood or sodium chloride-containing infusions can induce precipitation or alter tonicity; therefore concurrent administration is avoided except when compatibility studies under USP <790> are available.
In sugar-free confectionery and compressed mint manufacturing, mannitol is incorporated at 10–40% of total dry mass to reduce hygroscopicity, prevent surface graining, and maintain tablet edge definition. The compound is permitted as a direct food substance under 21 CFR 184.1095 and as additive E421 in the European Union. Because mannitol has a negative enthalpy of dissolution of approximately -121 J/g, its crystalline form produces a measurable cooling sensation when the compressed mint or chewing gum pellet dissolves in saliva. In sugar-free chewing gum, mannitol is blended with sorbitol and gum base in a sigma-blade mixer at 55–65 °C; mannitol reduces cold-flow and protects the coating from moisture bloom during subsequent panning. Dental-health labeling falls under 21 CFR 101.80 and requires that the food does not lower plaque pH below 5.7 in vivo; mannitol-containing sugar-free confectionery is formulated to meet this requirement, although the final label claim is product-specific. Compressed mint formulations are produced on rotary tablet presses at 15–35 kN using mannitol grades with bulk density above 0.50 g/mL to maintain uniform die filling. Mannitol is not the preferred polyol for high-boiled hard candy because its aqueous solubility at room temperature is below 25 g/100 mL, so the syrup would crystallize prematurely during vacuum cooking; its use is therefore confined to compressed mints, chewing gum coatings, and dry-blended tabletop sweeteners where low hygroscopicity is more valuable than high solubility.
Mannitol serves as a C2-symmetric chiral feedstock for double dehydration to 1,4:3,6-dianhydro-D-mannitol, commonly named isomannide, which is subsequently polycondensed into bio-based polyesters and polycarbonates. The stoichiometric conversion of mannitol C6H14O6 to isomannide C6H10O4 releases two equivalents of water and corresponds to a theoretical mass loss of 19.8%. Laboratory and pilot-scale dehydration is carried out in glass-lined batch reactors using sulfuric acid at 0.5–3.0 wt% or p-toluenesulfonic acid at 1–5 wt% as catalyst, with reaction temperatures between 120 °C and 160 °C and reduced pressure of 10–50 mbar to continuously strip water from the reaction mass. Selectivity is the dominant quality issue: incomplete dehydration produces monoanhydro mannitol intermediates, while overexposure to acid forms humin-like oligomers that darken the crude reaction product and poison later polymerization catalysts. The crude isomannide is neutralized, passed through ion-exchange resin, and refined by short-path distillation at pressures below 5 mbar; polymer-grade monomer typically requires transition-metal residues below 10 ppm and water content below 200 ppm by ISO 15512. Published data for continuous reactive extrusion of mannitol-to-isomannide in corotating twin-screw equipment is limited compared with sorbitol-based isosorbide production, so scale-up of this particular dehydration route remains a batch-controlled process. Terminal downstream products include chiral diester monomers for amorphous high-glass-transition polyesters, but each polymer specification must be validated against residual catalyst and color because mannitol-derived monomer lots showing absorbance above 0.15 AU at 420 nm are generally unsuitable for optical applications.
Mannitol dry powder for bronchial provocation testing is filled into hard hypromellose capsules as a micronized powder with a laser-diffraction d50 of 2–6 µm, delivered through a capsule-based dry powder inhaler. The diagnostic formulation is unusual because mannitol is not an excipient carrier but the active osmotic challenge: upon inhalation, the deposited particles raise airway surface liquid osmolality and provoke bronchoconstriction in susceptible patients, with a positive test defined as a reduction in forced expiratory volume in one second of 15% or more from baseline. Metered doses are administered in stepwise capsule strengths of 5 mg, 10 mg, 20 mg, and 40 mg, up to a cumulative dose of 635 mg. Delivered dose uniformity and aerodynamic particle size distribution are controlled by cascade impaction according to USP <601> and Ph. Eur. 2.9.18, while capsule content uniformity is assessed by high-performance liquid chromatography with refractive-index detection. The product must be stored at 15–30 °C with desiccant protection, because moisture uptake above 5% relative humidity shifts particle cohesion and reduces fine particle fraction below the target range. Capsule shell moisture barrier properties and inhaler piercing design both influence emitted dose; published production-scale data for this specific mannitol diagnostic powder is limited because the marketed device is supported by proprietary single-source manufacturing and device-specific in vitro correlation models.
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D-Mannitol is supplied as a white crystalline or spray-dried powder with molecular formula C6H14O6 and molecular weight 182.17 g/mol. The material is identified by CAS 69-65-8 and EINECS 200-711-8, and it is produced in multiple particle-engineered grades that differ in median particle size, bulk density, and compaction behavior. Pharmacopoeial grades are certified against USP-NF, Ph. Eur., and JP monographs; commercial model designations include Pearlitol 200SD, Pearlitol 300DC, Mannogem EZ, and Parteck M. In comparison with sorbitol, xylitol, and lactose, mannitol exhibits lower aqueous solubility, negligible hygroscopicity, and the absence of a reducing aldehyde group, which defines its utility in moisture-sensitive and amine-containing formulations.
Identity and purity are controlled through monograph limits that address melting range, optical rotation, loss on drying, residue on ignition, reducing sugars, chloride, sulfate, heavy metals, and, for parenteral grades, bacterial endotoxins. The melting range is 166–170 °C under USP-NF and 165–170 °C under Ph. Eur.; the specific rotation is +23° to +25° in both compendia. Loss on drying is limited to ≤0.3% in USP-NF and ≤0.5% in Ph. Eur.. Reducing sugars are controlled at ≤0.3%. The table below summarizes the principal compendial acceptance criteria.
| Attribute | USP-NF acceptance criterion | Ph. Eur. acceptance criterion |
|---|---|---|
| Appearance | White, crystalline powder or granules | White, crystalline powder or granules |
| Melting range | 166–170 °C | 165–170 °C |
| Specific rotation | +23° to +25° | +23° to +25° |
| Loss on drying | ≤0.3% | ≤0.5% |
| Reducing sugars | ≤0.3% | ≤0.3% |
| Residue on ignition | ≤0.1% | ≤0.1% |
| Bacterial endotoxins | Parenteral grades controlled under USP <85> | Parenteral grades controlled under Ph. Eur. 2.6.14 |
Commercial producer certificates of analysis typically report internal limits tighter than monograph values, with loss on drying at ≤0.2% maximum and residual reducing sugars below 0.1%. Elemental impurity control follows ICH Q3D; residual solvents are controlled under USP <467> when applicable. The specification profile for direct compression grades adds bulk density, tapped density, particle size distribution, and specific surface area, which are not identity tests but are critical for tablet weight uniformity and hopper discharge.
When direct compression is selected for moisture-sensitive actives, spray-dried mannitol is blended as a diluent-binder because the particles are porous and deformable under compaction. Commercial grades exhibit median particle sizes distributed between 100 µm and 500 µm by laser diffraction, with the finer Pearlitol 200SD and Parteck M 200 used for low-dose formulations and coarser Pearlitol 300DC, Pearlitol 400DC, and Mannogem EZ used for higher tablet weights. Powder flow, measured under USP <1174>, typically gives Carr index values of 15–20% and Hausner ratios of 1.15–1.20. Tablets compressed on rotary tablet presses at 5–25 kN show friability of 0.2–0.8% after 100 revolutions in USP <1216> and tensile strengths in the 1–3 MPa range, depending on grade and compression force; published data for specific API combinations are limited. Because mannitol is non-reducing, the diluent does not initiate Maillard degradation with primary or secondary amine active pharmaceutical ingredients, unlike lactose monohydrate.
Particle size distribution is controlled by sieving or laser diffraction. Fine crystalline powder grades such as Pearlitol 25C and Pearlitol 50C are selected for wet granulation and capsule filling; spray-dried grades such as Pearlitol 200SD and Parteck M 200 are selected for direct compression; coarse granular grades such as Pearlitol 400DC and Mannogem EZ are used in chewable tablets and sachets. Typical bulk densities range from 0.35 g/cm3 to 0.70 g/cm3, and tapped density values are measured under USP <616>. Coarse granular grades reduce dust and improve hopper discharge but exhibit lower specific surface area, which can reduce compact tensile strength at equivalent compression force. Published data for all equipment configurations are limited; manufacturer application sheets provide grade-specific compaction profiles.
Parenteral mannitol is manufactured as a sterile crystalline powder and formulated into 15% w/v, 20% w/v, and 25% w/v solutions for intravenous infusion. The 20% w/v concentration corresponds to an osmolarity of approximately 1098 mOsmol/L; 15% w/v and 25% w/v yield 823 mOsmol/L and 1372 mOsmol/L, respectively. Terminal sterilization is performed in an autoclave at 121 °C for 15 min; the solution is subsequently inspected for sub-visible particulates under USP <788> and for visible defects under USP <790>. Endotoxin levels are controlled under USP <85>, with the acceptance limit calculated from the maximum dose and route; low-endotoxin mannitol is required. Unlike sorbitol, mannitol is only minimally metabolized and undergoes glomerular filtration with limited tubular reabsorption, accounting for its osmotic diuretic action. Crystallization can occur in supersaturated solutions during chilled storage; if crystals appear, the container is warmed to 37–50 °C until dissolution and inspected before use.
In pharmaceutical analytical method development and lyophilized formulations, mannitol is used as a matrix component because its low ultraviolet absorbance above 210 nm permits detection of active pharmaceutical ingredients without interference. The absence of reducing groups means that mannitol can be used in freeze-dried cakes where reducing sugars would react with peptide lysine residues. For freeze-drying, mannitol is used at 5–20% w/v with controlled cooling to produce a crystalline cake; amorphous mannitol can recrystallize during storage and release water, which is a recognized stability defect. Annealing at -20 °C to -15 °C for 2–4 h is used to promote crystallization of the bulk mannitol phase in freeze-drying cycles and to reduce primary drying time.
In sugar-free confectionery and compressed mint applications, mannitol is used under food additive classification E 421 as a bulk sweetener and dusting powder. Its sweetness is approximately 0.5 relative to sucrose, lower than sorbitol at 0.6 and xylitol at 1.0. The endothermic dissolution produces a cooling sensation, although the perceived intensity is less than xylitol. Because mannitol is non-hygroscopic and has a critical relative humidity of approximately 85%, it does not absorb ambient moisture on production lines during compressed mint tableting. It is not fermented to a clinically significant extent by oral acidogenic bacteria, supporting its use in sugar-free chewing gum and lozenges. Regulatory authorizations include FDA 21 CFR 180.25 and the European Union food additive specification for E 421; JECFA has assigned an ADI of “not specified.”
Comparative stability data place mannitol between sorbitol and xylitol with respect to cooling effect and below both polyols in hygroscopicity and solubility. The matrix below summarizes differentiating properties. Sorbitol deliquesces at approximately 69% RH and is not suitable for effervescent or moisture-sensitive formulations without desiccant protection. Xylitol deliquesces near 79% RH and provides a stronger cooling effect but has a lower melting point. Lactose monohydrate is non-hygroscopic but reducing; mannitol is non-reducing and is therefore preferred when the formulation contains primary amine actives.
| Property | Mannitol | Sorbitol | Xylitol |
|---|---|---|---|
| Melting range | 166–170 °C | 94–96 °C | 92–94 °C |
| Aqueous solubility | 1 g in 5.5 mL water | 1 g in 0.45 mL water | 1 g in 0.65 mL water |
| Critical relative humidity at 25 °C | 85% | 69% | 79% |
| Sweetness relative to sucrose | 0.5 | 0.6 | 1.0 |
| Cooling effect in oral solids | Moderate endothermic | Low | Strong endothermic |
| Reducing capacity | Non-reducing | Non-reducing | Non-reducing |
Process boundaries for mannitol are set by its crystalline solid state and low aqueous solubility. In wet granulation, mannitol dissolves slowly; high-shear granulation with excess water produces hard, coarse granules and extended drying times. Direct compression and dry granulation avoid this limitation. Bulk storage of opened containers above 85% RH can cause surface moisture pickup and flow reduction; drying at 80–100 °C restores flow, but temperature exposure above 170 °C must be avoided due to melting and caramelization. Mannitol is not compatible with strong oxidizing agents at elevated process temperatures. In parenteral compounding, the final solution should be visually inspected after warming and must not be administered if crystals or visible particulate matter remain. These boundaries differentiate mannitol from sorbitol, which remains sticky under humid conditions, and from xylitol, which requires lower drying temperatures because of its 92–94 °C melting range.