In situ measurement of solvent-mediated phase transformations during dissolution testing

In this study, solvent-mediated phase transformations of theophylline (TP) and nitrofurantoin (NF) were measured in a channel flow intrinsic dissolution test system. The test set-up comprised simultaneous measurement of drug concentration in the dissolution medium (with UV-Vis spectrophotometry) and measurement of the solid-state form of the dissolving solid (in situ with Raman spectroscopy). The solid phase transformations were also investigated off-line with scanning electron microscopy. TP anhydrate underwent a transformation to TP monohydrate, and NF anhydrate (form beta) to NF monohydrate (form II). Transformation of TP anhydrate to TP monohydrate resulted in a clear decrease in the dissolution rate, while the transformation of NF anhydrate (form beta) to NF monohydrate (form II) could not be linked as clearly to changes in the dissolution rate. The transformation of TP was an order of magnitude faster than that of NF. The presence of a water absorbing excipient, microcrystalline cellulose, was found to delay the onset of the transformation of TP anhydrate. Combining the measurement of drug concentration in the dissolution medium with the solid phase measurement offers a deeper understanding of the solvent-mediated phase transformation phenomena during dissolution.     

Simultaneous UV Imaging and Raman Spectroscopy for the Measurement of Solvent-Mediated Phase Transformations During Dissolution Testing

The current work reports the simultaneous use of UV imaging and Raman spectroscopy for detailed characterization of drug dissolution behavior including solid-state phase transformations during dissolution. The dissolution of drug substances from compacts of sodium naproxen in 0.1 HCl as well as theophylline anhydrate and monohydrate in water was studied utilizing a flow-through setup. The decreases in dissolution rates with time observed by UV imaging were associated with concomitant solid form changes detected by Raman spectroscopy. Sodium naproxen and theophylline anhydrate were observed to convert to the more stable forms (naproxen, and theophylline monohydrate) within approximately 5 min. Interestingly, the new approach revealed that three intermediate forms are involved in the dissolution process prior to the appearance of the neutral naproxen during dissolution in an acidic medium. The combination of UV imaging and Raman spectroscopy offers a detailed characterization of drug dissolution behavior in a time-effective and sample-sparing manner. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1149–1156, 2014     

Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy

Amorphous drugs have a higher kinetic solubility and dissolution rate than their crystalline counterparts. However, this advantage is lost if the amorphous form converts to the stable crystalline form during the dissolution as the dissolution rate will gradually change to that of the crystalline form. The purpose of this study was to use in situ Raman spectroscopy in combination with either partial least squares discriminant analysis (PLS-DA) or partial least squares (PLS) regression analysis to monitor as well as quantify the solid-phase transitions that take place during the dissolution of two amorphous drugs, indomethacin (IMC) and carbamazepine (CBZ). The dissolution rate was higher from amorphous IMC compared to the crystalline α- and γ-forms. However, the dissolution rate started to slow down during the experiment. In situ Raman analysis verified that at that time point the sample started to crystallize to the α-form. Amorphous CBZ instantly started to crystallize upon contact with the dissolution medium. The transition from the amorphous form to CBZ dihydrate appears to go through the anhydrate form I. Based on the PLS analysis the amount of form I formed in the sample during the dissolution affected the dissolution rate. Raman spectroscopy combined with PLS-DA was also more sensitive to the solid-state changes than X-ray powder diffraction (XRPD) and was able to detect changes in the solid-state that could not be detected with XRPD.     

Instability in Theophylline and Carbamazepine Hydrate Tablets: Cocrystal Formation Due to Release of Lattice Water

Purpose

To demonstrate two sequential solid-state reactions in intact tablets: dehydration of active pharmaceutical ingredient (API), and cocrystal formation between the anhydrous API and a second formulation component mediated by the released water. To evaluate the implication of this in situ phase transformation on the tablet dissolution behavior.

Methods

Tablets containing theophylline monohydrate (TPM) and anhydrous citric acid (CA) were stored at 40°C in sealed polyester pouches and the relative humidity in the headspace above the tablet was continuously measured. Dehydration to anhydrous theophylline (TPA) and the product appearance (TPA-CA cocrystal) were simultaneously monitored by powder X-ray diffractometry. Carbamazepine dihydrate and nicotinamide formed the second model system.

Results

The water of crystallization released by TPM dehydration was followed first by deliquescence of citric acid, evident from the headspace relative humidity (~ 68%; 40°C), and then the formation of TPA-CA cocrystal in intact tablets. The noncovalent synthesis resulted in a pronounced decrease in the dissolution rate of theophylline from the tablets. Similarly, the water released by dehydration of carbamazepine dihydrate caused the cocrystallization reaction between anhydrous carbamazepine and nicotinamide.

Conclusions

The water released by API dehydration mediated cocrystal formation in intact tablets and affected dissolution behavior.     

Investigating the relationship between drug distribution in solid lipid matrices and dissolution behaviour using raman spectroscopy and mapping

In this study, in situ and mapping Raman spectroscopic measurements were used to investigate the physical structure of solid lipid extrudates and relate the structure to dissolution behaviour. Theophylline anhydrate was extruded with tripalmitin, with and without the water‐soluble polymer, polyethylene glycol 10000. Raman mapping of the extrudate cores revealed that drug particles of diverse size were dispersed in a continuous lipid phase with or without polyethylene glycol. At the surface, there was evidence of more mixing between the components. Previous characterisation by other methods suggested that the extrudate surface is covered predominantly by lipid, and the Raman mapping suggested that such a layer is in general less than a few micrometres thick. Nevertheless, the lipid layer dramatically reduced the drug dissolution rate. The extrudate cores were also mapped after a period of dissolution testing, and there was no evidence of a uniformly receding drug boundary in the extrudates during drug release. In situ Raman spectroscopy analysis during dissolution testing revealed that the drug distribution in the extrudate affected the formation of theophylline monohydrate. However, the drug release rate was primarily determined directly by drug distribution, with the solid‐state behaviour of the drug having a smaller influence. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1464–1475, 2010     

Use of Glancing Angle X-Ray Powder Diffractometry to Depth-Profile Phase Transformations During Dissolution of Indomethacin and Theophylline Tablets

PURPOSE: The purpose of this study was (i) to develop glancing angle x-ray powder diffractometry (XRD) as a method for profiling phase transformations as a function of tablet depth; and (ii) to apply this technique to (a) study indomethacin crystallization during dissolution of partially amorphous indomethacin tablets and to (b) profile anhydrate --> hydrate transformations during dissolution of theophylline tablets. METHODS: The intrinsic dissolution rates of indomethacin and theophylline were determined after different pharmaceutical processing steps. Phase transformations during dissolution were evaluated by various techniques. Transformation in the bulk and on the tablet surface was characterized by conventional XRD and scanning electron microscopy, respectively. Glancing angle XRD enabled us to profile these transformations as a function of depth from the tablet surface. RESULTS: Pharmaceutical processing resulted in a decrease in crystallinity of both indomethacin and theophylline. When placed in contact with the dissolution medium, while indomethacin recrystallized, theophylline anhydrate rapidly converted to theophylline monohydrate. Due to intimate contact with the dissolution medium, drug transformation occurred to a greater extent at or near the tablet surface. Glancing angle XRD enabled us to depth profile the extent of phase transformations as a function of the distance from the tablet surface. The processed sample (both indomethacin and theophylline) transformed more rapidly than did the corresponding unprocessed drug. Several challenges associated with the glancing angle technique, that is, the effects of sorbed water, phase transformations during the experimental timescale, and the influence of phase transformation on penetration depth, were addressed. CONCLUSIONS: Increased solubility, and consequently dissolution rate, is one of the potential advantages of metastable phases. This advantage is negated if, during dissolution, the metastable to stable transformation rate > dissolution rate. Glancing angle XRD enabled us to quantify and thereby profile phase transformations as a function of compact depth. The technique has potential utility in monitoring surface reactions, both chemical decomposition and physical transformations, in pharmaceutical systems.     

Influence of the Solid Form of Siramesine Hydrochloride on its Behavior in Aqueous Environments

Purpose  To study the influence of solid form on the behavior of the salt siramesine hydrochloride in aqueous environments. Methods  The solubilities and dissolution rates of siramesine hydrochloride anhydrate and monohydrate were determined at pH 3.4 and 6.4, and precipitates were examined by X-ray powder diffraction. The mechanism of anhydrate–hydrate conversion was investigated by optical microscopy, and wet massing of the anhydrate was carried out using water and 60% (v/v) ethanol separately as granulation liquids. The wet masses were analyzed using Raman microscopy. Results  At pH 3.4 the anhydrate and monohydrate salts exhibited similar dissolution profiles. At pH 6.4 both the anhydrate and monohydrate salts formed supersaturated solutions of high apparent solubility. From the anhydrate solution, precipitation of the free base occurred, while the solution of the monohydrate salt remained in the supersaturated state. This resulted in a superior dissolution profile of the monohydrate salt. Microscopy and wet massing experiments showed that the anhydrate–hydrate conversion of siramesine hydrochloride was solution-mediated and dissolution-controlled. Conclusion  During development of a formulation based on the anhydrate salt, the risk of processing-induced transformation to the monohydrate form as well as precipitation of the free base should be considered.     

Rotating-Disk Dissolution Kinetics of Nitrofurantoin Anhydrate and Monohydrate at Various Temperatures

The dissolution behavior of nitrofurantoin anhydrate and monohydrate in JP XI, second fluid (pH 6.8) was investigated at various temperatures using a dispersed-amount method and a rotating-disk method. The initial dissolution process of the monohydrate obtained by the rotating-disk method followed the Noyes–Whitney–Nernst equation, but that of the anhydrate did not. The initial dissolution process of the anhydrate was analyzed by a dissolution kinetics equation involving the phase transformation process from anhydrate to monohydrate. The maximal concentration, the dissolution rate constant, and the rate constant of the phase transition process were estimated. The thermodynamic parameters for the dissolution processes of the anhydrate and monohydrate were obtained from van't Hoff plots and Arrhenius plots, respectively. The results of the intrinsic solubility and dissolution parameters of anhydrate and mono-hydrate suggest the possibility that the difference in the dissolution rates of the anhydrate and monohydrate affect the bioavailability of nitrofurantoin preparation. Information on the dissolution behavior of nitrofurantoin pseudopolymorphs is therefore useful for designing high-quality preparations.     

In situ monitoring of carbamazepine–nicotinamide cocrystal intrinsic dissolution behaviour

Cocrystals have shown huge potential to improve the dissolution rate and absorption of a poorly water soluble drug. However, solution mediated phase transformation of cocrystals could greatly reduce the enhancement of its apparent solubility and dissolution rate. The aim of this study is to gain a deep understanding of the phase transition behaviour of cocrystals during dissolution and to investigate the improvement of dissolution rate. Dissolution and transformation behaviour of carbamazepine–nicotinamide (CBZ–NIC) cocrystal, physical mixture and different forms of carbamazepine: form I (CBZ I), form III (CBZ III) and dihydrate (CBZ DH) were studied by different in situ techniques of UV imaging and Raman spectroscopy. It has been found that compared with CBZ III and I, the rate of intrinsic dissolution rate (IDR) of CBZ–NIC cocrystal decreases slowly during dissolution, indicating the rate of crystallisation of CBZ DH from the solution is slow. In situ solid-state characterisation has shown the evolution of conversion of CBZ–NIC cocrystal and polymorphs to its dihydrate form. The study has shown that in situ UV imaging and Raman spectroscopy with a complementary technique of SEM can provide an in depth understanding during dissolution of cocrystals.     

A discriminatory intrinsic dissolution study using UV area imaging analysis to gain additional insights into the dissolution behaviour of active pharmaceutical ingredients

For efficient and effective drug development it is desirable to acquire a deep understanding of the dissolution behaviour of potential candidate drugs and their physical forms as early as possible and with the limited amounts of material that are available at that time. Using 3-10mg sample quantities, the ability of a UV imaging system is investigated to provide deep mechanistic insight into the intrinsic dissolution profiling of a range of compounds and physical forms assessed under flow conditions. Physical forms of indomethacin, theophylline and ibuprofen were compressed and their solid-state form confirmed before and after compression with X-ray methods and/or Raman spectroscopy. Intrinsic dissolution rates (IDRs) were determined using the compact's UV-imaging profile. The ratio in the IDRs for theophylline anhydrate over hydrate was 2.1 and the ratio for the alpha form of indomethacin over the gamma form was approximately 1.7. The discriminatory power of the novel UV area visualisation approach was shown to be high in that process-induced solid-state dissolution differences post-micronisation could be detected. Additionally, the scale-down system was able to visualise a previously observed increase in ibuprofen IDR with an increase in concentration of sodium dodecyl sulphate. The mechanistic dissolution insights from the visualisation approach are evident.     

In Situ Monitoring and Modeling of the Solution-Mediated Polymorphic Transformation of Rifampicin: From Form II to Form I

In this article, the solution-mediated polymorphic transformation of rifampicin was investigated and simulated in 3 solvents at 30°C. The solid-state form I and form II of rifampicin was characterized by powder X-ray diffraction, scanning electron microscopy, thermogravimetric analysis, Raman spectroscopy, and Fourier transform infrared spectroscopy (FTIR). To explore the relative stability, solubility data of form I and form II of rifampicin in butan-1-ol were determined using a dynamical method. In addition, Raman spectroscopy and focused beam reflectance measurement were used to in situ monitor the transformation of rifampicin from form II to form I. The liquid state concentration of rifampicin was measured by UV spectroscopic method. To investigate the effect of solvent on transformation, the transformation experiments were carried out in 3 solvents. Furthermore, a mathematical model was built to describe the kinetics of dissolution, nucleation, and growth processes during transformation by using experimental data. By combination of experimental and simulation results, it was found that the transformation process of rifampicin is controlled by dissolution of form II in heptane, whereas the transformation in hexane and octane was firstly controlled by dissolution of solid-state form and then controlled by growth of form I.     

Dissolution of theophylline monohydrate and anhydrous theophylline in buffer solutions

The dissolution kinetics of theophylline monohydrate and anhydrous theophylline were investigated with a rotating-disk apparatus in buffer solutions at 298 K under sink conditions. The observed dissolution rate of theophylline monohydrate under various conditions agreed well with predictions based on the Extended Simultaneous Chemical Reaction and Dissolution concept. Below 337 K, anhydrous theophylline is converted to theophylline monohydrate in contact with water. The dissolution profile of anhydrous theophylline can be divided into three phases: a pre-transformation phase: anhydrous theophylline dissolves; the transformation phase, during which its dissolution rate drops to the level of the theophylline monohydrate dissolution rate; and steady state, at which the dissolution rate of anhydrous theophylline equals the dissolution rate of theophylline monohydrate. The presence of theophylline monohydrate crystals at the dissolving surface was confirmed by IR spectroscopy and microscopic observation. The length of the transformation phase, depending on the characteristics of the diffusion boundary layer, varied with the experimental conditions (e.g., pH and rotation speed). It was concluded that during the dissolution process the disk is covered with theophylline monohydrate crystals that precipitate from the supersaturated medium adjacent to the disk surface, and that crystallization of theophylline monohydrate is a precipitation process controlled by hydrodynamic and diffusion parameters.     

Physical characterization of erythromycin: anhydrate, monohydrate, and dihydrate crystalline solids

Hot-stage microscopy, thermoanalytical methods, and X-ray powder diffraction were used to demonstrate that crystalline erythromycin dihydrate converts to the crystalline anhydrate via a noncrystalline intermediate. X-ray powder diffraction, IR spectral, thermogravimetric, and differential thermal analyses were used to characterize the monohydrate material. The flow interrupt technique, a procedure recently developed to deal with low surface area samples, was employed successfully in obtaining isotherms and specific surface areas for the monohydrate and anhydrate. The relative dissolution rates of the various hydrates were determined in an aqueous solution (0.01 M phosphate buffer, pH 7.5) at 37 degrees. The results showed a significant difference in the dissolution rate of the dihydrate compared to the monohydrate and anhydrate.     

Manipulating Theophylline Monohydrate Formation During High-Shear Wet Granulation Through Improved Understanding of the Role of Pharmaceutical Excipients

Purpose To investigate the effect of common pharmaceutical excipients on the kinetics of theophylline monohydrate formation during high-shear wet granulation. Materials and methods A mixture of anhydrous theophylline and the excipient was granulated in a high-shear granulator, using water as the granulation liquid. Non-contact Raman spectroscopy was used to monitor the rate of transformation of anhydrate to hydrate during the granulation process. The kinetics of conversion was also monitored in slurries of theophylline whereby the excipients were added to the aqueous phase. Optical microscopy was used to visualize the transformation and to measure the linear growth rates of hydrate crystals in the presence and absence of the excipients. Results At pharmaceutically relevant amounts of excipient, the transformation kinetics of theophylline was unchanged for the majority of excipients tested. However, when granulating with low concentrations of some commonly used polymeric binders, the transformation kinetics could be significantly retarded. For example, methylcellulose polymers delayed both the onset of hydrate formation as well as retarding the transformation rate. When 0.3% (w/w) of hydroxypropyl methylcellulose was added to a model formulation containing 30% (w/w) theophylline anhydrous, the formation of the monohydrate could be completely prevented over the time period of the granulation experiment, without significantly affecting the granular properties. Microscopic observations of hydrate formation in the presence of the polymer revealed that the polymers that inhibited hydrate formation reduced the hydrate crystal growth rates and influenced hydrate morphology. Conclusions Raman spectroscopy is a useful technique to monitor hydrate formation during wet granulation. Some commonly used polymeric pharmaceutical excipients can be used to manipulate theophylline hydrate formation in aqueous pharmaceutical environments. These excipients may affect either the nucleation and/or the growth of the hydrate phase.     

In vitro controlled release of antihypertensive drugs intercalated into unmodified SBA-15 and MgO modified SBA-15 matrices

The aim of the present study was two-fold: (1) to investigate the effect of pH and presence of surfactant sodium lauryl sulphate (SLS) on the solubility and dissolution rate of two solid-state forms of piroxicam (PRX), anhydrate (PRXAH) and monohydrate (PRXMH), and (2) to quantitatively assess the solid-phase transformation of PRXAH to PRXMH in slurry with a special interest to the impact on the solubility and dissolution behavior of the drug. X-ray powder diffractometry (XRPD), Raman spectroscopy and scanning electron microscopy (SEM) were used for characterization of the solid-state forms. Phase transformation was monitored in slurry by means of in-line Raman spectroscopy, and the partial least squares (PLS) regression model was used for predicting the amount of PRXMH. The results showed that the solubility and dissolution rate of PRXAH were higher compared to PRXMH at different pHs. The pH and presence of SLS together affected the solubility and dissolution rate of different PRX forms. The lowest solubility values and dissolution rates for PRX forms were observed in distilled water (pH 5.6) at 37 °C. The changes in the dissolution rate could be explained by the hydrate formation during solubility testing. The rate of hydrate formation was also dependent on the pH of the dissolution medium.     

Dehydration kinetics of neotame monohydrate

The dehydration of neotame monohydrate was monitored at various temperatures by differential scanning calorimetry (DSC), thermogravimetry (TGA), hot-stage microscopy (HSM), powder X-ray diffractometry (PXRD), and (13)C solid-state nuclear magnetic resonance (SSNMR) spectroscopy. This work emphasizes kinetic analysis of isothermal TGA data by fitting to various solid-state reaction models and by model-free kinetic treatment. The dehydration of neotame monohydrate follows the kinetics of a two-dimensional phase boundary reaction (R2) at 40-50 degrees C with an activation energy of 75 +/- 9 kJ/mol, agreeing well with 60-80 kJ/mol from model-free kinetics. At a low heating rate in DSC and TGA, neotame monohydrate undergoes dehydration to produce anhydrate Form E, which then converts to anhydrate Form A, followed by the melting of A. Neotame monohydrate under dry nitrogen purge at 50 mL/min undergoes partial isothermal dehydration at 50 degrees C to produce neotame anhydrate Form A. When neotame monohydrate is heated very slowly from 50 to 65-70 degrees C over 24 h, pure Form A is obtained.     

Solid-state characterization of fluconazole

Two polymorphs and three solvates of fluconazole were isolated and characterized by x-ray powder diffractometry, IR spectroscopy, differential scanning calorimetry (DSC), thermogravimetry, and their dissolution rates. The different forms were prepared by crystallization of the original powder in different solvents at different cooling rates. X-ray diffraction patterns of the five solid modifications exhibited substantial differences in both the intensity and position of the peaks. FTIR spectra of the five different solid-state modifications also exhibited differences in the peaks' positions and intensities. DSC thermogram of anhydrate form I showed a single melting point at 139.2 degrees C. Anhydrate form II showed two endothermic peaks at 136.5 and 139.2 degrees C and one exothermic peak in between. The DSC thermogram of acetone 1/4 solvate exhibited two endothermic peaks at 75.5 and 139.2 degrees C. Benzene 1/7 solvate exhibited two endothermic peaks at 131.5 and 138.8 degrees C. Hydrate E exhibited two endothermic peaks at 102.7 and 139.2 degrees C. The DSC thermogram of anhydrate form II showed that this form is sensitive to the application of a mechanical force. The solubility study showed that anhydrate form II and acetone 1/4 solvate have higher solubilities than anhydrate form I while benzene 1/7 solvate and monohydrate have lower solubilities than anhydrate form I. The intrinsic dissolution study confirmed these results.     

Monitoring of multiple solid-state transformations at tablet surfaces using multi-series near-infrared hyperspectral imaging and multivariate curve resolution

The assessment of the solid-state stability of active pharmaceutical ingredient (API) and/or excipients in solid dosage forms during manufacturing and storage is mandatory for safeguarding quality of the final products. In this work, the solid-state transformations in tablets prepared as blends of piroxicam monohydrate, polyvinylpyrrolidone and the lactose forms monohydrate or anhydrate were studied when the tablets were exposed to the 23–120 °C range. Multi-series near-infrared hyperspectral images were obtained from the surface of each sample for unveiling the local evolution of the solid-state transformations. The preprocessed spectra from the images (dataset) were arranged in augmented matrices, according to the composition of the tablets, and the profile of the overlapped compounds (relative concentration) along the solid-state transformations in the pixels was resolved by using multivariate curve resolution – alternating least squares (MCR-ALS). Therefore, the dehydration of piroxicam and lactose monohydrates could be mapped separately in the samples (explained variances by the models >96%) even when both compounds were being transformed simultaneously (80–120 °C). The images reproduced the same trends obtained from thermogravimetric analysis of the tablets, with the advantage that the pixel-to-pixel heterogeneity of each compound at the surface of the tablets was highlighted.     

Effects of excipients on hydrate formation in wet masses containing theophylline

Transformations between solid phases in dosage forms can lead to instability in drug release. Thus, it is important to understand mechanisms and kinetics of phase transformations and factors that may influence them. During wet granulation theophylline shows pseudopolymorphic changes that may alter its dissolution rate. The aim of this study was to investigate whether excipients, such as alpha-lactose monohydrate or the highly water absorbing silicified microcrystalline cellulose (SMCC) can influence the hydrate formation of theophylline. In particular, the aim was to study if SMCC offers protection against the formation of theophylline monohydrate relative to alpha-lactose monohydrate in wet masses after an overnight equilibration and the stability of final granules during controlled storage. In addition, the aim was to study the use of spectroscopic methods to identify hydrate formation in the formulations containing excipients. Off-line evaluation of materials was performed using X-ray powder diffractometry, near infrared and Raman spectroscopy. alpha-Lactose monohydrate with minimal water absorbing potential was not able to prevent but enhanced hydrate formation of theophylline. Even though SMCC is able to take large amounts of water into its internal structure, it was able to inhibit the formation of theophylline monohydrate only at low moisture contents, not at the amounts of water needed to form granules. Both the spectroscopic methods used could identify the hydrate formation even though there were excipients in the formulation.     

Effect of Environmental Humidity on the Transformation Pathway of Nitrofurantoin Modifications During Grinding and the Physicochemical Properties of Ground Products

Abstract— The effect of humidity on the physicochemical properties of nitrofurantoin anhydrate and monohydrate during grinding in a humidity-controlled system was investigated using X-ray diffraction analysis, IR spectroscopy, thermal analysis and scanning electron microscopy. Anhydrate and monohydrate were transformed into a noncrystalline solid and a stable monohydrate, respectively, during grinding in a closed system. During grinding in an open system, in which the humidity level of the air was controlled (5, 50 and 75% r.h.), the anhydrate absorbed moisture from the supplied air and water content was increased at 75% r.h.; thereafter the compound was transformed into monohydrate II. The anhydrate did not absorb at 5 or 50% r.h. and was transformed into a noncrystalline solid. Monohydrate I desorbed crystal water during grinding at 5% r.h. and was transformed into a noncrystalline solid. However, monohydrate I was transformed into monohydrate II at 50 and 75% r.h. without desorption of crystal water. These results suggest that the solid-state transformation of nitrofurantoin during grinding depends upon the environmental humidity.