Pure Mannitol Research Articles

Shape-stable phase change composite for highly efficiency thermal energy storage using metal-organic framework-encapsulated yeast as porous carbon carrier

Technical barriers including the poor thermal conductivity, low energy conversion efficiency, and melting leakage hindered the large-scale storage of waste heat and solar energy by the shape-stable phase change materials (ss-PCMs). To address the challenges mentioned above, a high-performance ss-PCM is fabricated using the thermal conducive 3D interconnected scaffold that derived from a biomimetically grown yeast-templated zeolitic imidazolate framework-8 (ZIF-8) precursor. After carbonization, the morphology and porosity-controlled bio-inspired derived [email protected] porous carbon (DYC) exhibited unique porous skeleton, which allowing high capillary adsorption and effective chemical interaction for mannitol storage. The obtained DYC/mannitol ss-PCM exhibited high thermal conductivity (1.17 W/mK), high relative enthalpy efficiency (98.96%), and outstanding stability and recyclability. Meanwhile, compared with the pure mannitol, the supercooling degree of the novel DYC/mannitol was decreased by 18.42%. All findings suggested that the ss-PCM by yeast-templated MOFs derived hierarchical porous carbon has good application prospects in high-density energy storage.

Formation of delta-mannitol by co-spray drying: enhancing the tabletability of paracetamol/mannitol formulations

δ-mannitol is a metastable polymorph of mannitol, known for its superior tableting properties. However, there is no easy, reproducible and scalable production method for δ-mannitol. It was evaluated whether δ-mannitol could be formed via co-spray drying with an API exhibiting tabletability issues, to improve the API tabletability in a one-step process prior to compaction. Aqueous suspensions with paracetamol and β-mannitol were co-spray dried. Raman spectroscopy was used to identify the mannitol polymorphs. In these formulations, paracetamol was the key factor to allow the formation of δ-mannitol since no traces of the δ-polymorph could be detected after spray drying a pure mannitol feed. The presence of δ-mannitol after co-spray drying was confirmed even for low paracetamol/mannitol ratios (1:99). The δ-mannitol content varied depending on the process drying parameters, predominantly by the airflow. A lower airflow promoted the formation of δ-mannitol, while more α-mannitol was formed when applying a higher airflow. The starting material, β-mannitol, was often no longer detectable by Raman spectroscopy. The tabletability of the spray dried powders clearly improved in association with the δ-mannitol concentration. The co-processed powders showed superior tabletability in comparison with physical mixtures of the starting materials. Harder tablets with a maximal tensile strength of 2.9 MPa at a main compression pressure of 247 MPa were achieved.

Chromatographic separation of mannitol from mixtures of other carbohydrates in aqueous solutions

The isolation of mannitol from natural sources, e.g. from plant extracts or broths, requires considerable time and effort. The separation of mannitol from aqueous solutions containing also glucose, fructose, and sucrose was tested using discontinuous preparative anion- and cation-exchange chromatography. The suitability of the application in the separation of carbohydrates and especially mannitol was tested under various conditions and using three different types of ion-exchangers. The effect of sorbent regeneration and modification on the separation was also examined using different concentrations and volumes of chemical agents. The fractions collected after the discontinuous chromatography were analysed on the content of mannitol by the high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) method. The successful isolation of pure mannitol fraction, using water as a mobile phase and a combination of sodium chloride and hydroxide for sorbent regeneration, was achieved only on anion-exchange chromatography.

A Robust and Highly Selective Catalytic System of Copper-Silica Nanocomposite and 1-Butanol in Fructose Hydrogenation to Mannitol.

We report for the first time the selective production of mannitol, a low-calorie sweetener and an important pharmaceutical ingredient, from fructose using Cu-SiO2 nanocomposite as catalyst and 1-butanol as solvent. When compared with water and ethanol, a lower fructose solubility was achieved in 1-butanol, which caused a lower fructose conversion and higher mannitol selectivity by reducing formation of side products. Among various Cu-based catalysts in 1-butanol, Cu(80)-SiO2 nanocomposite gave an unprecedented mannitol (83 %) and sorbitol (15 %) yield at 120 °C, 35 bar H2 , and 10 h reaction time. More importantly, this catalyst did not show any Cu leaching and its physicochemical properties were maintained after liquid-phase fructose hydrogenation whereas other Cu-based catalysts such as Cu(32)-Cr2 O and Cu(66)-ZnO did show significant leaching of Cu and Cr. Thus, Cu(80)-SiO2 nanocomposite and 1-butanol are regarded as a robust and highly efficient catalytic system for the selective hydrogenation of fructose to mannitol. Also, density functional theory calculations supported that in addition to the stable initial structure of adsorbed fructose, the mannitol pathway was more thermodynamically favorable than the sorbitol pathway. Notably, the highly pure mannitol (99 %) could be recovered from the sorbitol-containing 1-butanol solution by simple filtration. Therefore, the present protocol is a novel and effective method to produce pure mannitol from fructose in both an environmental and an industrial context.

Evaluation of Two Extraction Methods for the Analysis of Hydrophilic Low Molecular Weight Compounds from Ganoderma lucidum Spores and Antiproliferative Activity on Human Cell Lines

Background: The genus Ganoderma includes about 80 species of mushrooms. Ganoderma lucidum is the best-known fungal species in mycotherapy and likely has the highest number of studies. Numerous bioactive compounds seem to be responsible for its beneficial effects; in particular, triterpenes, peptidoglycans and polysaccharides are the main physiologically active constituents. The aim of the present work is to identify the main bioactive components in aqueous extracts of G. lucidum spores obtained by two different extraction processes. Methods: The spores were at first extracted by a Soxhlet apparatus with n-hexane and the aqueous solutions were submitted to two different procedures: hot water extraction (HWE) and rapid solid-liquid dynamic extraction (RSLDE) using the Naviglio extractor. The extracts were then dialyzed to separate the compounds with higher molecular weight from polar compounds with lower molecular weight. The aqueous extracts and dialyzed fractions were tested on two human cell lines: human colonic epithelial cells (Caco-2) and human colorectal carcinoma cells (HTC-116). Results: GC-MS and NMR data revealed the presence of a mixture of glucose and mannitol in ratio 3.7:1 in the most active fraction. Conclusions: The outside dialysis phase of RSLDE extract seems to be particularly cytotoxic for HTC-116 and, interestingly, solutions with different concentrations of pure mannitol showed cytotoxic activity against this cell line too, although to a lesser extent.

Native starch as in situ binder for continuous twin screw wet granulation.

The use of native starch as in situ binder in a continuous twin screw wet granulation process was studied. Gelatinization of pea starch occurred in the barrel of the granulator using a poorly soluble excipient (anhydrous dicalcium phosphate), but the degree of gelatinization depended on the liquid-to-solid ratio, the granule heating and the screw configuration. Furthermore, the degree of starch gelatinization was correlated with the granule quality: higher binder efficiency was observed in runs where starch was more gelatinized. SEM and PLOM images showed experimental runs which resulted in completely gelatinized starch. Other starch types (maize, potato and wheat starch) could also be gelatinized when processed above a critical barrel temperature for gelatinization. This barrel temperature was different for all starches. In situ starch gelatinization was also investigated in combination with a highly soluble excipient (mannitol). The lower granule friability observed using pure mannitol compared to a mannitol/starch mixture indicated that starch did not contribute to the binding, hence starch did not gelatinize during processing. The study showed that native starch can be considered as a promising in situ binder for continuous twin screw wet granulation of a poorly soluble formulation.

The influence of mannitol on morphology and disintegration of spray-dried nano-embedded microparticles

Nano-embedded microparticles represent a promising approach to deliver nanoparticles to the lungs. Microparticles with an appropriate aerodynamic diameter enable an application by dry powder inhaler and the transport of nanoparticles into the airways. By disintegration after deposition, nanoparticles can be released to exhibit their advantages such as a sustained drug release and delivery of the drug across the mucus barrier. The use of an appropriate matrix excipient to embed the nanoparticles is essential for the necessary disintegration and release of nanoparticles.In this context we investigated the influence of mannitol on the morphology, aerodynamic properties and disintegration behavior of nano-embedded microparticles.PLGA nanoparticles and mannitol were spray dried each as sole component and in combination in three different ratios. An influence of the mannitol content on the morphology was observed. Pure mannitol microparticles were solid and spherical, while the addition of nanoparticles resulted in raisin-shaped hollow particles. The different morphologies can be explained by diffusion processes of the compounds described by the Péclet-number. All powders showed suitable aerodynamic properties. By dispersion of the powders in simulated lung fluid, initial nanoparticle sizes could be recovered for samples containing mannitol. The fraction of redispersed nanoparticles was increased with increasing mannitol content. To evaluate the disintegration under conditions with higher comparability to the in vivo situation, spray-dried powders were exposed to >90% relative humidity. The disintegration behavior was monitored by analyzing roughness values by white light interferometry and supporting SEM imaging. The exposure to high relative humidity was shown to be sufficient for disintegration of the microparticles containing mannitol, releasing morphologically unchanged nanoparticles. With increasing mannitol content, the disintegration occurred faster and to a higher degree. Under these conditions, microparticles only composed of nanoparticles did not disintegrate.By enabling the release of nanoparticles from nano-embedded microparticles, mannitol was shown to be an ideal excipient to convert nanoparticles by spray drying into an inhalable dry power formulation.

A pragmatic approach for engineering porous mannitol and mechanistic evaluation of particle performance

The importance of mannitol has increased recently as an emerging diluent for orodispersible dosage forms. The study aims to prepare spray dried mannitol retaining high porosity and mechanical strength for the development of orally disintegrating tablets (ODTs).Aqueous feed of d-mannitol (10% w/v) comprising ammonium bicarbonate, NH4HCO3 (5% w/v) as pore former was spray dried at inlet temperature of 110–170°C. Compacts were prepared at 151MPa and characterized for porosity, hardness and disintegration time. Particle morphology and drying mechanisms were studied using thermal (HSM, DSC and TGA) and polymorphic (XRD) methods.Tablet porosity increased from 0.20±0.002 for pure mannitol to 0.53±0.03 using fabricated porous mannitol. Disintegration time dropped by 50–77% from 135±5.29s for pure mannitol to 75.33±2.52–31.67±1.53s for mannitol 110–170°C. Hardness increased by 150% at 110°C (258.67±28.89N) and 30% at 150°C (152.70±10.58N) compared to pure mannitol tablets (104.17±1.70N). Increasing inlet temperature resulted in reducing tablet hardness due to generation of ‘micro-sponge’-like particles exhibiting significant elastic recovery. Impact of mannitol polymorphism on plasticity/elasticity cannot be ruled out as a mixture of α and β polymorphs formed upon spray drying.

Evaluation of terrestrial plants extracts for uranium sorption and characterization of potent phytoconstituents

Sorption capacity of four plants (Funaria hygrometrica, Musa acuminata, Brassica juncea and Helianthus annuus) extracts/fractions for uranium, a radionuclide was investigated by EDXRF and tracer studies. The maximum sorption capacity, i.e., 100% (complete sorption) was observed in case of Musa acuminata extract and fractions. Carbohydrate, proteins, phenolics and flavonoids contents in the active fraction (having maximum sorption capacity) were also determined. Further purification of the most active fraction provided three pure molecules, mannitol, sorbitol and oxo-linked potassium oxalate. The characterization of isolated molecules was achieved by using FTIR, NMR, GC-MS, MS-MS, and by single crystal-XRD analysis. Of three molecules, oxo-linked potassium oxalate was observed to have 100% sorption activity. Possible binding mechanism of active molecule with the uranyl cation has been purposed.

Estimation of thermal endurance of multicomponent sugar alcohols as phase change materials

This study investigates the thermal endurance of sugar alcohols and their eutectic mixtures as phase-change materials (PCMs). Three sugar alcohols (mannitol, dulcitol, and inositol) and their eutectic mixtures were selected as the PCM candidates. First, the thermophysical properties of the single- and multicomponent sugar alcohols were characterized using differential scanning calorimetry. Second, the thermal endurance of the PCM candidates was estimated by constant-temperature kinetics based on the degradation of the latent heat of the PCM candidates. The results showed that mannitol, dulcitol, inositol, and their eutectic mixtures had melting points and latent heats of over 423 K and 200 kJ/kg, respectively. The kinetic analysis of the PCM candidates showed that the first-order reaction rate equation was suitable for analyzing the degradation of the latent heat of the sugar alcohols. The degradation periods increased with decrease of melting temperatures of each sugar alcohol. In particular, the dulcitol/mannitol eutectic mixture showed the longest degradation periods of 9817 ks, which is 5.68 and 6.85 times greater than those of pure mannitol and dulcitol, respectively. These observations indicated that eutectic mixtures of sugar alcohols were promising and alternative PCM candidates in the 373–473 K temperature range.

Conception, preparation and properties of functional carrier particles for pulmonary drug delivery

BackgroundThe effectiveness of aerosol therapy is significantly reduced by the mucus layer covering the airways of the tracheobronchial tree. According to the present concept, drug particles are delivered to the lung together with the functional carrier particle that facilitates both the drug transport into the lungs and the penetration of deposited particles through the mucus. The approach of manufacturing multi-component powders with mucoactive compounds and anti-asthmatic medicines (DSCG) bound together in a single particle is additionally considered. MethodsPowders were produced with the spray-drying technique from aqueous precursor solutions containing pure low molecular weight dextran, pure mannitol and dextran/mannitol–N-acetyl cysteine (NAC) mixtures (4:1 and 1:1). NAC has been selected for this purpose as a compound, which is known to be mucolytic. Dextran and mannitol are potentially applicable in the field of inhalation drug delivery. They have been used as stabilizers of functional carrier particles. Powders were characterized for their yield and physicochemical properties including: morphology (SEM), moisture content and thermal properties (DSC). Aerosol performance was determined with NGI impactor after standardized aerosolization of the produced powders in a commercial DPI. ResultsParticle size distributions of dextran–NAC powders were characterized by high fine particle fraction (45–62%), which assures good particle deposition in the lower airways. The thermodynamic properties of the powders based on the temperature of the glass transition Tg (50–63°C) suggest the required stability during storage at moderate humidity. ConclusionsPreliminary examination of the required properties of these particles confirms their potential as functional carriers for pulmonary drug delivery.

Chemical imaging of pharmaceutical granules by Raman global illumination and near-infrared mapping platforms

Raman global illumination and near-infrared (NIR) mapping instruments were used to chemically image pharmaceutical granules obtained by the wet granulation process in order to determine whether the API was mixed with the major excipient or granulates on its own. The granules were randomly distributed onto a microscope slide and an average area of about 3.5 mm × 3.5 mm, covering 50–100 granules, was analyzed by both instruments. Light microscopy images of the separated granules were collected before the spectroscopic data acquisition. Both Raman and NIR signals of API and major excipient (mannitol) were easily detected by both techniques which allowed the chemical structure of the granules to be characterised. Most of the granules were found to contain both API and mannitol but pure mannitol and a few pure API granules were also identified. Raman global illumination was found to provide a comprehensive insight into chemical structure of the granules being able to more clearly determine the API in comparison with NIR mapping. Owing to the differences in shapes of the particles and reflection characteristics, visual microscopy and methods based on reflection can be potentially useful for analyzing this particular formulation.

Cohesive, multicomponent, dense powder flow characterization by NIR

Non-aerated powder flows are frequently encountered in downstream pharmaceutical processes. Such flows occur at the entrance of powder compression units, and their characteristics are of great interest because any powder agglomeration or segregation can be detrimental to the quality of the final solid oral dosage form. This work was aimed at developing a process analytical technology (PAT) method, based on near-infrared spectroscopy (NIR) for the in-line powder flow characterization of pharmaceutical formulations. An Ibuprofen drug formulation was selected for study. A bench-scale hopper system was assembled to monitor powder flow behaviour. An in-line commercial NIR Axsun spectrometer and probe were chosen to collect in-line spectral data on dense, multicomponent, non-aerated powder flow prior to compression. Spectra were collected on flowing mannitol and pharmaceutical product blends. A specially designed, non-contact sampling interface allowed the collection of representative process powder flow spectra without affecting blend uniformity. A partial least squares chemometric model was developed for laboratory-prepared samples, to quantitatively determine the flowing powder's active pharmaceutical ingredient (API) level. Static sample spectra and flowing pure mannitol spectra proved to have a high degree of reproducibility. The model's standard error of calibration was 2.95% of the API level with a R 2 of 0.991. Flowing blend powder spectra and API estimates showed variations consistent with those seen in model samples. The average values for flowing pharmaceutical blends were close to the API concentration, indicating that the proposed procedure was statistically acceptable. The model is considered very promising, and some improvements would lead to its final acceptance at production scale as a PAT tool.

Lactose-based molecular alloys obtained by solid state vitrification

In this paper, we report the possibility to form glassy amorphous molecular alloys α-lactose/mannitol and α-lactose/budesonide by milling together pure crystalline powders of α-lactose and mannitol on the one hand, and pure crystalline powders of α-lactose and budesonide on the other hand. It is also shown that upon milling, pure mannitol undergoes a polymorphic transformation from the stable form β towards the metastable form α, while pure budesonide undergoes a complete amorphization. The results have been established by differential scanning calorimetry and by powder X-ray diffraction.

Formation of lactose-mannitol molecular alloys by solid state vitrification

In this paper, we report the possibility to form glassy molecular alloys (α-lactose) 1− x (mannitol) x for x<0.5 by co-milling two crystalline powders of pure α-lactose and pure mannitol β. The results have been established by differential scanning calorimetry and by powder X-ray diffraction. The concentration dependence of the glass transition temperature is found to obey the Gordon Taylor rule expected for regular solutions. It is also shown that the milling of pure mannitol β ( x=1) leads to a polymorphic transformation towards the metastable form α of mannitol.

Strength and morphology of solid bridges in dry granules of pharmaceutical powders

This is an experimental study of the tensile strength of solid bridges between primary particles comprising granules of lactose or mannitol. We report on two systems: granules prepared with ethanol granulating solutions, in which the base powders were at most sparingly soluble, and aqueous granulating solutions, in which the base powder solubility was large. Both systems were studied with and without hydroxypropylcellulose (HPC) or polyvinylpyrrolidone (PVP) or surfactants (Triton-X100, sodium lauryl sulfate or polysorbate 80) added to the granulating solution. The interparticle bridge strength was determined from the granule crush strength with a simple model that assumes that solid bridges form by evaporation of solvent from liquid bridges that maintain their shape during drying. Lactose granules prepared with pure ethanol are very weak, with crush strength comparable to that predicted by JKR theory, consistent with its negligible solubility. Mannitol, which is sparingly soluble, forms granules with bridge strength similar to the theoretical (Griffith) strength of a pure mannitol. Addition of HPC or PVP to the granulating solution produces bridges with strength comparable to that of pure polymer films. In comparison, the behavior of granules prepared with aqueous granulating solutions was much more complex due to the high saturation concentration of base powder. Granules produced with pure water had bridge strength approximately 20% of the theoretical strength. Addition of HPC or PVP to lactose granules increased the bridge strength modestly, but the strength was much smaller than that of the corresponding pure polymer films. Addition of HPC to mannitol granules had little effect on bridge strength, while PVP reduced bridge strength by approximately 30%. Addition of surfactants to the granulating solution also reduced dry bridge strength. These results reflect the complex microstructure and resulting mechanical properties of dry bridges produced by coprecipitation of the sugars and polymers (or surfactants).

Crystallization of D-mannitol in binary mixtures with NaCl: phase diagram and polymorphism.

To study the crystallization, polymorphism, and phase behavior of D-mannitol in binary mixtures with NaCl to better understand their interactions in frozen aqueous solutions. Differential scanning calorimetry, hot-stage microscopy, Raman microscopy, and variable-temperature X-ray diffractometry were used to characterize D-mannitol-NaCl mixtures. NaCl and D-mannitol exhibited significant melt miscibility (up to 7.5% w/w or 0.20 mole fraction of NaCl) and a eutectic phase diagram (eutectic composition 7.5% w/w NaCl; eutectic temperature 150 degrees C for the alpha and beta polymorphs of D-mannitol and 139 degrees C for the delta). The presence of NaCl did not prevent mannitol from crystallizing but, depending on sample size, affected the polymorph crystallized: below 10 mg, delta was obtained; above 100 mg, alpha was obtained. Pure mannitol crystallized under the same conditions first as the delta polymorph and then as the a polymorph, with the latter nucleating on the former. KCl showed similar eutectic points and melt miscibility with D-mannitol as NaCl. LiCl yielded lower eutectic melting points, inhibited the crystallization of D-mannitol during cooling, and enabled the observation of its glass transition. Despite their structural dissimilarity, significant melt miscibility exists between D-mannitol and NaCl. Their phase diagram has been determined and features polymorph-dependent eutectic points. NaCl influences the polymorphic behavior of mannitol, and the effect is linked to the crystallization of mannitol in two polymorphic stages.

Evolution and structure of drying material bridges of pharmaceutical excipients: studies on a microscope slide

An experimental procedure was developed to study directly the process by which liquid bridges between small particles in a granule form and solidify. The evolution of saturated solutions of such pharmaceutical excipients as lactose and mannitol in a liquid bridge was studied on a system situated on a microscope slide. Solidification and crystallization kinetics and phase composition during and immediately following bridge formation were observed directly. It was shown that bridges on the microscope slide and in the granule behave very much the same regardless of the different length and diffusion-scales of the two systems. We found that solid bridge formation takes place in several consecutive but distinct steps. In the case of lactose, considerable shrinkage of the initial liquid bridge takes place prior to the onset of crystallization. Further bridge solidification at ambient conditions occurs via simultaneous crystallization and vitrification within minutes. As a result, a “solid” bridge usually contains both a crystalline and a non-crystalline phase, the crystalline phase being predominately α-lactose monohydrate. Most of the non-crystalline phase eventually converts to crystalline β-lactose but the process may take many hours or even days. Results for this process are compared for samples obtained from different manufacturers of commercially available lactose. In the case of mannitol, different polymorphic forms crystallize as the drying/crystallization process progresses. A formed “solid” bridge usually contains several polymorphs of mannitol. The relevance of the behavior of the two model systems (pure lactose and pure mannitol) to a real granulation and tabletting process is discussed.

Spray‐freeze‐drying for protein powder preparation: Particle characterization and a case study with trypsinogen stability

This work investigates the use of spray freeze‐drying (SFD) to produce protein loaded particles suitable for epidermal delivery. In the first part of the study, the effects of formulation and process conditions on particle properties are examined. Aqueous solutions of trehalose produce SFD particles in the size range 20–80 μm, with a smooth, textured surface, but having high internal porosity. The latter was visualized using SEM and a novel particle embedding and sectioning technique. Use of an annealing step during the freeze‐drying cycle caused the particles to shrink, reducing hereby porosity and also the measured rate of moisture uptake into these amorphous particles. SFD pure mannitol was approximately 40% amorphous, but not hygroscopic. Incorporation of dextran 37,500 into a combined amorphous trehalose/mannitol formulation led to increased particle shrinkage and lower particle porosity on annealing. The model protein trypsinogen lost approximately 15% activity during SFD of solutions containing 50 mg/mL protein, but was only marginally aggregated (1.4%). It is suggested that trypsinogen forms an irreversible partially unfolded state or molten globule on SFD/rehydration. The pure protein was also partially inactivated without aggregation during atomization into air. Surprisingly, neither activity loss nor aggregation were detected on atomization of the protein solution into liquid nitrogen. Quench‐freezing of small droplets may reverse the partial unfolding of trypsinogen occurring on atomization into air. The origin of the trypsinogen inactivation during SFD must therefore be the subsequent freeze‐drying step of this multistep process. Isolated freeze drying of trypsinogen produces strong aggregation and equivalent inactivation. This result suggests that trypsinogen behaves differently during freeze drying from frozen droplets and from bulk solution in a vial. In the former case the protein forms an irreversible partially unfolded state, whereas in the latter case aggregates are formed. Trypsinogen inactivation during SFD could be completely prevented by the presence of trehalose in the formulation. Electron Spectroscopy for Chemical Analysis (ESCA) showed a high surface excess of the protein in the SFD particles, which was reduced on inclusion of Polysorbate 80, but not trehalose. Taken together, these results help to elucidate the complex destabilization behavior of trypsinogen during SFD. © 2002 Wiley‐Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91:2122–2139, 2002

Existence of a mannitol hydrate during freeze‐drying and practical implications

We report thermal and crystallographic evidence for a previously unknown mannitol hydrate that is formed in the process of freeze‐drying. The mannitol hydrate was produced by freeze‐drying pure mannitol solutions (1–4% w/v) using the following cycle: (1) equilibration at −5 °C for 1 h; (2) freezing at −40 °C; (3) primary drying at −10 °C for 15 h; and (4) secondary drying at 10 °C for 2 h and then 25 °C for 5 h. This crystal form was also observed upon freeze‐drying in the presence of sorbitol (1% w/v). The mannitol hydrate showed a distinct X‐ray powder diffraction pattern, low melting point, and steplike desolvation behavior that is characteristic of crystalline hydrates. The mannitol hydrate was found to be metastable, converting to anhydrous polymorphs of mannitol upon heating and exposure to moisture. The amount of the mannitol hydrate varied significantly from vial to vial, even within the same batch. The formation of mannitol hydrate has several potential consequences: (1) reduced drying rate; (2) redistribution of the residual hydrate water during accelerated storage to the amorphous drug; and (3) vial‐to‐vial variation of the moisture level.