Mannitol Polymorphs Research Articles

Rapid polymorphic screening using sessile microdroplets: competitive nucleation of mannitol polymorphs

Using microdroplets, we developed an approach to rapidly measure the nucleation statistics of polymorphs. It can be useful in the routine screening of pharmaceutical solid forms, and in the study of the competitive nature of polymorphic nucleation.

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.

Mannitol Polymorphs as Carrier in DPIs Formulations: Isolation Characterization and Performance.

The search for best performing carriers for dry powder inhalers is getting a great deal of interest to overcome the limitations posed by lactose. The aerosolization of adhesive mixtures between a carrier and a micronized drug is strongly influenced by the carrier solid-state properties. This work aimed at crystallizing kinetically stable D-mannitol polymorphs and at investigating their aerosolization performance when used in adhesive mixtures with two model drugs (salbutamol sulphate, SS, and budesonide, BUD) using a median and median/high resistance inhaler. A further goal was to assess in vitro the cytocompatibility of the produced polymer-doped mannitol polymorphs toward two lung epithelial cell lines. Kinetically stable (up to 12 months under accelerate conditions) α, and δ mannitol forms were crystallized in the presence of 2% w/w PVA and 1% w/w PVP respectively. These solid phases were compared with the β form and lactose as references. The solid-state properties of crystallized mannitol significantly affected aerosolization behavior, with the δ form affording the worst fine particle fraction with both the hydrophilic (9.3 and 6.5%) and the lipophilic (19.6 and 32%) model drugs, while α and β forms behaved in the same manner (11–13% for SS; 53–58% for BUD) and better than lactose (8 and 13% for SS; 26 and 39% for BUD). Recrystallized mannitol, but also PVA and PVP, proved to be safe excipients toward lung cell lines. We concluded that, also for mannitol, the physicochemical properties stemming from different crystal structures represent a tool for modulating carrier-drug interaction and, in turn, aerosolization performance.

Effect of cyclophosphamide on the solid form of mannitol during lyophilization

Mannitol is a commonly used bulking agent in lyophilized formulations. It can crystallize into multiple solid forms during lyophilization thereby exhibiting phase heterogeneity and variability in product performance. In this manuscript, we studied the effect of cyclophosphamide (CPA), an anticancer drug, on the solid form of mannitol during lyophilization from aqueous solutions. Freeze-concentration studies were performed in the DSC while lyophilization was performed in a lab scale freeze dryer.DSC experiments revealed two-stage crystallization of mannitol (1.5% w/v) during freeze-concentration, evident as two distinct exothermic events (at −18.2°C and −30°C) in the cooling curve. This was complemented by two eutectic melting endotherms in the subsequent heating curve. Addition of CPA (4.0% w/v) completely inhibited the exotherm at −18.2°C, but enhanced the enthalpy of exotherm at −30°C by five folds. Likewise, only one eutectic melting endotherm was observed in the subsequent heating curve. Lyophilization of the solution containing only mannitol, yielded a mixture of β- (major) and δ- (minor) polymorphs of mannitol. However, in the presence of CPA, only δ-polymorph was observed in the lyophilized sample.This selective favoring of the metastable δ-polymorph over the stable β-polymorph, was explained by altered freezing kinetics of the solution in presence of CPA. The study provides mechanistic insights into solute crystallization behaviour during lyophilization of multi-component systems.

Impact of vacuum-induced surface freezing on inter- and intra-vial heterogeneity

This paper aimed to study the impact of freezing on both within-batch (inter-vial) and within-product (intra-vial) heterogeneity. This analysis has been carried out using two freezing protocols, the conventional shelf-ramped method and the Vacuum Induced Surface Freezing, and placebo formulations containing both crystallizing (mannitol) and amorphous (lactose and sucrose) excipients. The freezing conditions (i.e., the temperature of freezing, the temperature and time of the equilibration phase, and the filling volume) were found to have a dramatic impact on both the within-batch and the within-product homogeneity. Overall, we observed that the control of freezing can effectively minimize the variability in product characteristics, and moisture content, within the same batch. In addition to more uniform production, the control of freezing was found to be fundamental to achieve a more uniform product than that produced by the shelf-ramped freezing method. The influence of the freezing protocol on the crystallization process of mannitol was also investigated, showing that the temperature of freezing plays a key role in the formation of the mannitol polymorphs.

High spectral specificity of local chemical components characterization with multichannel shift-excitation Raman spectroscopy

Raman spectroscopy has emerged as a promising tool for its noninvasive and nondestructive characterization of local chemical structures. However, spectrally overlapping components prevent the specific identification of hyperfine molecular information of different substances, because of limitations in the spectral resolving power. The challenge is to find a way of preserving scattered photons and retrieving hidden/buried Raman signatures to take full advantage of its chemical specificity. Here, we demonstrate a multichannel acquisition framework based on shift-excitation and slit-modulation, followed by mathematical post-processing, which enables a significant improvement in the spectral specificity of Raman characterization. The present technique, termed shift-excitation blind super-resolution Raman spectroscopy (SEBSR), uses multiple degraded spectra to beat the dispersion-loss trade-off and facilitate high-resolution applications. It overcomes a fundamental problem that has previously plagued high-resolution Raman spectroscopy: fine spectral resolution requires large dispersion, which is accompanied by extreme optical loss. Applicability is demonstrated by the perfect recovery of fine structure of the C-Cl bending mode as well as the clear discrimination of different polymorphs of mannitol. Due to its enhanced discrimination capability, this method offers a feasible route at encouraging a broader range of applications in analytical chemistry, materials and biomedicine.

Low-frequency shift dispersive Raman spectroscopy for the analysis of respirable dosage forms.

A high performance Raman system equipped with a CCD (charged coupled device) sensor and recently developed optical filter technology is described. It provides high sensitivity, high resolution, and access to low-frequency vibrations enabling resolution of spectral features due to lattice vibrational modes and internal vibrational modes, greatly improving the ability to detect small changes due to variations in the three dimensional molecular arrangement, e.g., during loss of crystallinity. Applications to solid state analysis, such as solid phase identification and differentiation of glycopyrronium bromide and formoterol fumarate in pharmaceutical powders, and identification of active pharmaceutical ingredients, e.g., salmeterol xinafoate, fluticasone propionate, mometasone furoate, and salbutamol sulphate, as well as excipients, e.g., amino acids, in different formulations, are presented. For the first time, low-frequency shift Raman spectra of mannitol polymorphs were measured and used for solid phase identification. Unambiguous identification of two similar bronchodilator metered dose inhalers, Ventolin(®) HFA and Airomir(®), was accomplished. The low-frequency shift Raman signals can be used for the analysis of crystallinity of small samples (<5mg) of respiratory dosage forms in a multi-component formulation matrix containing less than 3% by weight of the component of interest.

Spontaneous Polymorphic Nucleation ofd-Mannitol in Aqueous Solution Monitored with Raman Spectroscopy and FBRM

The spontaneous nucleation of d-mannitol polymorphs at different initial concentrations in an aqueous solution was investigated. Two in situ process analytical technology (PAT) tools, Raman spectroscopy and focused beam reflectance measurement (FBRM), were combined to monitor the process, allowing instantaneous detection of polymorphs after nucleation. It was found that the stable β form of mannitol was favored at low initial concentrations, whereas the metastable α form nucleated at high concentrations and the metastable δ polymorph crystallized when the concentration was in the medium level. To help understand this phenomenon, the thermodynamic and kinetic characteristics of different polymorphs were analyzed. The solubility of the two metastable forms was determined by an innovative method with the aid of Raman spectroscopy, whereas the interfacial energy between polymorphs and the bulk solution were obtained from the induction time measurements. Consequently, the critical excess free energy and other critical parameters associated with the nucleation of various polymorphs were calculated. It was concluded that the nucleation of mannitol polymorphs from an aqueous solution depends on both the thermodynamic and kinetic properties, with the importance of each highly dependent on the supersaturation prevailing in the system.

Particle size dependence of polymorphism in spray-dried mannitol

The purpose of this project was to investigate the polymorphic variation of spray-dried mannitol model formulations as a function of particle size. Spray-dried powders with varying mannitol polymorphs were produced by adjusting process parameters, using co-solvent and adding a model protein (lysozyme). The obtained dry powders were dispersed into different size fractions using a Next Generation Pharmaceutical Impactor. The mannitol polymorphs in the different size fractions were analyzed using X-ray powder diffraction (XRPD), Fourier transform near infrared (FT-NIR) and Raman spectroscopy. Chemometrics was applied to interpret the FT-NIR and Raman spectra. Different spray-dried mannitol systems were established in this study, which contain mixtures of α- and β-mannitol. The XRPD, FT-NIR and Raman studies showed that the use of ethanol as a co-solvent increased the amount of α-mannitol in the smaller particles. The addition of low levels of lysozyme resulted in more α-mannitol in the smaller particles, while an increased content of lysozyme in spray-dried mannitol system resulted in more β-mannitol in the smaller particle size fraction. In conclusion spray-drying of mannitol based formulations can result in variation in the solid state composition of mannitol as a function of particle size. This finding may be clinically relevant and underlines the need for proper process control of inhalable dry powder produced by spray-drying.

The Impact of Operating Parameters on the Polymorphic Transformation of d-Mannitol Characterized in Situ with Raman Spectroscopy, FBRM, and PVM

d-Mannitol is a typical polymorphic crystalline compound. In this paper, this polymorphic transformation from the α to the β form of mannitol is monitored by in situ Raman spectroscopy, focused beam reflectance measurement (FBRM) and particle vision measurement (PVM). The standard Raman spectra of the two polymorphs of mannitol were determined and the characteristic peaks for the different polymorphs were chosen to track the transformation process. By combining Raman with FBRM and PVM, relationships between fine particles and metastable form dissolution and also between coarse particles and stable form crystallization could be defined. The solution-mediated polymorphic transformation mechanism was confirmed by these in situ tools. The effect of temperature, solvent and substrate mass on the transformation time was also investigated. It was noted that operating temperature and solvent composition have a significant influence on the transformation time.

Terahertz spectroscopy to identify the polymorphs in freeze-dried mannitol

We show how terahertz time-domain spectroscopy (THz-TDS) in the range from 0.1 to 7.5 THz can be used to identify the polymorphs of Mannitol, a frequently used excipient in the freeze drying industry. The results are subsequently used to study the effect that different freeze drying techniques have on the formation of these polymorphs. We find that, depending on the freeze-drying technique, the Mannitol either crystallizes in the δ form, or in a mixture of both the δ form and the β form. The results are in agreement with conventional X-ray diffraction measurements used to identify the polymorphs. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:932–940, 2010

Freezing step controls the mannitol phase composition heterogeneity

Freeze-dried samples were prepared from D-mannitol solution by selected freezing conditions. Crystalline structures of prepared samples were determined by XRD analysis, and distributions of the various crystal structures of mannitol were obtained for each sample. It was found that the amount of each polymorph was quite well correlated to the freezing conditions, namely the ice crystal nucleation temperature and the cooling rate. In case of samples prepared at fast cooling rates, the samples where the ice crystals nucleated at higher temperature contained much more stable form than the samples nucleated at lower temperature. Besides, the samples prepared at slow cooling rates predominantly contained stable crystalline forms despite of the variation of nucleation temperatures. Moreover, the experimental results also indicated that the various polymorphs were also distributed vertically through the sample along the direction of the heat flux during freezing. The tendency of the polymorph distribution through the freeze-dried cake was also elucidated by using the simulated temperature profiles during freezing. Thus, the profiles of mannitol polymorphs after the freezing derived from the temperature distributions could predict the global tendency of polymorphism behaviour, and, consequently, would be useful to achieve quality control of freeze-dried formulations.

Cross-Nucleation between d-Mannitol Polymorphs in Seeded Crystallization

Seeding the liquid of d-mannitol with its polymorphs (α, β, and δ) revealed several cases of cross-nucleation between polymorphs. Only seeds of the α polymorph (the structure of the intermediate thermodynamic stability and the fastest growth rate) yielded the same polymorph in new growth. Seeds of the δ polymorph yielded the α polymorph in new growth. Seeds of the β polymorph yielded the β polymorph in new growth at small undercoolings (a few degrees below its melting point); at lower temperatures, the α polymorph nucleated on β seeds and its amount in the product increased with decreasing temperature. Seeding with single crystals of the β polymorph (rods elongated along c) showed that the orientation of the seed crystal affected how much the seed polymorph could grow before cross-nucleation occurred. Cross-nucleation makes seeding ineffective for achieving polymorphic selectivity but is sometimes avoidable by choosing suitable crystallization conditions.

Impact of freezing procedure and annealing on the physico-chemical properties and the formation of mannitol hydrate in mannitol–sucrose–NaCl formulations

The goal was to investigate the impact of NaCl on the physico-chemical properties of mannitol–sucrose formulations during freezing and drying, with special focus on mannitol hydrate formation. Differential scanning calorimetry (DSC) and low-temperature X-ray powder diffraction (LTXRD) were used to study the frozen solutions. After lyophilization the products were analyzed with DSC, temperature-modulated DSC (TMDSC), X-ray powder diffraction (XRD) and Karl-Fischer titration. DSC showed an inhibition of mannitol crystallization by sucrose and NaCl during freezing. The glass transitions of the maximally freeze-concentrated solutions ( Tg′) were lowered by both mannitol and NaCl. By the application of an annealing step during lyophilization mannitol crystallinity could be increased. However, lyophilization with an annealing step promoted the formation of mannitol hydrate, which is known to undergo conversion into the anhydrous polymorphs of mannitol upon storage. LTXRD revealed that mannitol hydrate was formed at temperatures below −30 °C, but not at −27 °C. The tendency that mannitol hydrate is predominantly formed at lower temperature was confirmed by XRD of lyophilized products, produced at different annealing temperatures. For the development of lyophilization cycles the lowered Tg′, as well as the tendency to mannitol hydrate formation predominantly at lower temperature needs to be considered.

Red-Excitation Dispersive Raman Spectroscopy is a Suitable Technique for Solid-State Analysis of Respirable Pharmaceutical Powders

Dispersive Raman spectroscopy with excitation by a red diode laser is suitable for quantitative crystallinity measurements in powders for pulmonary drug delivery. In spray-dried mixtures of salmon calcitonin and mannitol, all three crystalline polymorphs of mannitol and amorphous mannitol were unambiguously identified and their mass fractions were measured with a limit of quantification of about 5%. The instrument design offered high sensitivity and adequate background suppression, resulting in a low limit of detection in the range of 0.01% to 1%. This spectroscopy method has significant advantages over established techniques regarding specificity, sensitivity, and sample requirements.

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.

Quantitative analysis of mannitol polymorphs. X-ray powder diffractometry—exploring preferred orientation effects

Mannitol is a polymorphic pharmaceutical excipient, which commonly exists in three forms: alpha, beta and delta. Each polymorph has a needle-like morphology, which can give preferred orientation effects when analysed by X-ray powder diffractometry (XRPD) thus providing difficulties for quantitative XRPD assessments. The occurrence of preferred orientation may be demonstrated by sample rotation and the consequent effects on X-ray data can be minimised by reducing the particle size. Using two particle size ranges (<125 and 125–500 μm), binary mixtures of beta and delta mannitol were prepared and the delta component was quantified. Samples were assayed in either a static or rotating sampling accessory. Rotation and reducing the particle size range to <125 μm halved the limits of detection and quantitation to 1 and 3.6%, respectively. Numerous potential sources of assay errors were investigated; sample packing and mixing errors contributed the greatest source of variation. However, the rotation of samples for both particle size ranges reduced the majority of assay errors examined. This study shows that coupling sample rotation with a particle size reduction minimises preferred orientation effects on assay accuracy, allowing discrimination of two very similar polymorphs at around the 1% level.

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.