In-line monitoring of hydrate formation during wet granulation using Raman spectroscopy

Process-induced transformations are very important to control during pharmaceutical manufacturing because they may change the properties of the active pharmaceutical ingredient in the drug product, compromising therapeutic efficacy. One process that may facilitate a process-induced transformation is high-shear wet granulation. In this study, the feasibility of Raman spectroscopy for in-line monitoring of the transformation of theophylline anhydrous to theophylline monohydrate during high-shear wet granulation has been evaluated. The midpoint of conversion occurred 3 min after the binder solution was added. The effects of several processing parameters were also examined, including mixing speed and monohydrate seeding. Mixing speed had the greatest effect on the transformation, where an increase in mixing speed shortened the onset time and increased the rate of transformation. In contrast, seeding with monohydrate or changing the way in which the binder was incorporated into the granules did not affect the transformation profile. The transformation kinetics observed during wet granulation were compared with those generated by a simple model describing the solvent-mediated transformation of theophylline in solution. In conclusion, these studies show that Raman spectroscopy can be used for in-line monitoring of solid-state transformations during wet granulation. In addition, for this particular compound, a simple solvent-mediated transformation model has been shown to be useful for estimating the time scale for hydrate formation during high-shear wet granulation.     

Physical stability of crystal hydrates and their anhydrates in the presence of excipients

There are few studies in the literature that deal with the effect of excipients on the kinetics of vapor phase induced hydrate-anhydrate phase transformations. The main purpose of this study was to probe the phase stability of hydrate-anhydrate systems in the presence of hygroscopic and nonhygroscopic excipients following exposure to either dehydrating or hydrating conditions. Physical mixtures and compacts of model hydrate formers (theophylline and carbamazepine) and excipients (mannitol, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP) K12 and K90) were stored at 22 degrees C and varying relative humidities. Raman spectroscopy was used to monitor the kinetics of transformation between hydrate and anhydrate. In general, excipients were found either to have no effect or to promote dehydration. For hydrate formation, excipients could accelerate, retard, or have no influence on hydration kinetics. MCC was found to have only minimal effects on either the dehydration or hydration kinetics of model compounds, whereas mannitol enhanced dehydration but had little effect on hydration. Different PVP grades showed a variety effects: PVPK12 greatly enhanced the dehydration of both theophylline monohydrate (MT) and carbamazepine dihydrate (DC). PVPK90 also enhanced the dehydration of DC, but had a negligible effect on MT. For hydrate formation, PVPK12 was found to have a retarding effect on theophylline anhydrous (AT) transformation, but enhanced the conversion of carbamazepine anhydrous (AC) to DC, PVPK90 also retarded the hydration of AT, but had no effect on AC. Optical microscopy and X-ray powder diffraction studies suggested that PVP (in particular K12), when stored at high RH, was able to result in the partial dissolution of the active pharmaceutical ingredient and hence changed the hydration process from a solid state to a solution-mediated transformation. In summary, the effect of excipients on the kinetics of dehydration and hydration is complex and needs be rationalized in terms of several excipient properties including physical state, chemical composition, and the possibility of specific API-excipient interactions. It is concluded that a multitude of factors will dictate, and often complicate, the final effect of excipients on the phase transformation kinetics of hydrate formers.     

Role of excipients in hydrate formation kinetics of theophylline in wet masses studied by near-infrared spectroscopy.

Hydrate formation is a phase transition, which can occur during wet granulation. This kind of processing-induced transformation (PIT) can influence the quality of a finished product. The aim of the study was to investigate the effect of excipients on the kinetics of hydrate formation in wet masses. Anhydrous theophylline was chosen as the hydrate-forming model drug compound and two excipients, silicified microcrystalline cellulose (SMCC) and alpha-lactose monohydrate, with different water absorbing properties, were used in formulation. An early stage of wet massing was studied with anhydrous theophylline and its 1:1 (w/w) mixtures with alpha-lactose monohydrate and SMCC with 0.1g/g of purified water. The changes in the state of water were monitored using near-infrared spectroscopy, and the conversion of the crystal structure was verified using X-ray powder diffraction (XRPD). SMCC decreased the hydrate formation rate by absorbing water, but did not inhibit it. The results suggest that alpha-lactose monohydrate slightly increased the hydrate formation rate in comparison with a mass comprising only anhydrous theophylline.     

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.     

Manipulating Hydrate Formation During High Shear Wet Granulation Using Polymeric Excipients

Active pharmaceutical ingredients (API) can undergo an anhydrate to hydrate transformation during wet granulation and this transformation may either result in mixed crystalline forms or an unwanted form in the final drug product. Previous studies have shown that it may be possible to inhibit this transformation with polymeric excipients. In this study, three model compounds, caffeine (CAF), carbamazepine (CBZ), and sulfaguanidine (SGN), were subjected to high shear wet granulation and phase transformations were monitored using in-line Raman spectroscopy. Wet granulation was performed in the presence and absence of various polymeric excipients to determine the extent of the inhibitory effects. Although several polymers had some retardation effect, cross-linked poly(acrylic) acid was found to completely inhibit the CAF transformation and both hydroxypropyl methylcellulose and cross-linked poly(acrylic) acid completely inhibited the CBZ transformation. For SGN, transformation to the hydrate was rapid, even in the presence of the polymers. The observed inhibitory effects were attributed to either specific interactions between the polymer and the API crystal or substantial water absorption by the polymer. There was also evidence from physical property testing that the inclusion of a small amount of inhibitory polymer did not significantly change the compaction or flow behavior of the final granulation. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4670–4683, 2009     

Influence of polymeric excipients on crystal hydrate formation kinetics in aqueous slurries

Crystalline anhydrous active pharmaceutical ingredients (APIs) can potentially transform to the hydrate form during manufacturing processes involving water. The ability to understand and manipulate these transformations is important to maintain control of the solid state form of the API. The influence of various polymeric excipients on the anhydrate to hydrate transformation of caffeine, carbamazepine, and sulfaguanidine was investigated in this study. The transformation of the APIs in aqueous slurries was monitored using in-line Raman measurements and the resultant kinetic profiles provided insight into the inhibitory ability of the polymers investigated. The results showed that cross-linked poly(acrylic acid) inhibited the caffeine transformation and hydroxypropyl methylcellulose inhibited the carbamazepine transformation. None of the polymers tested were able to inhibit the sulfaguanidine transformation although some polymers were able to reduce the rate of the transformation with poly(vinylpyrrolidone) showing the greatest effect. It was found that the inhibitory polymers were able to either reduce crystal growth rates and/or increase the induction time preceding the nucleation event.     

Processing-induced phase transitions of theophylline--implications on the dissolution of theophylline tablets

Aqueous wet massing of stable anhydrous theophylline (A) with polyvinylpyrrolidone (PVP) resulted in its complete transformation to theophylline monohydrate (M). Drying at 45 degrees C, resulted in the formation of metastable anhydrous theophylline (A*) which then transformed to A. PVP, a known crystallization inhibitor, was effective in inhibiting the A* --> A transition. The higher molecular weight polymer, PVP K90, was more effective in inhibiting the A* --> A transition as compared to PVP K17. The disappearance of M, and the formation of A* and A was simultaneously monitored by XRD. An increase in the drying temperature from 45 to 55 degrees C accelerated the A* --> A transition. In granules prepared by the high-shear process, approximately 50% of theophylline existed as A and the rest as A*. In contrast, the fluid-bed granulation process yielded granules containing only A. Thus, the physical form of theophylline in tablets was influenced by the molecular weight of the binding agent, the granulation method, and the drying temperature. Using A as the starting material, tablets were manufactured by high-shear aqueous wet granulation process and the A* content was quantified. These tablets were stored under various relative humidity (RH) conditions at 25 degrees C for 2 weeks. Storage at RH >or= 33% caused complete A* --> A conversion accompanied by a pronounced decrease in the initial dissolution rate indicating that phase transitions during processing and storage can have a significant influence on product performance.     

Comparison of torque measurements and near-infrared spectroscopy in characterization of a wet granulation process

The purpose of this study was to compare impeller torque measurements and near-infrared (NIR) spectroscopy in the characterization of the water addition phase of a wet granulation process. Additionally, the effect of hydrate formation during granulation on the impeller torque was investigated. Anhydrous theophylline, alpha-lactose monohydrate, and microcrystalline cellulose (MCC) were used as materials for the study. The materials and mixtures of them were granulated using purified water in a small-scale high-shear mixer. The impeller torque was registered and NIR spectra of wet samples were recorded at-line. The torque and the NIR baseline-corrected water absorbances increased with increasing water content. A plateau in the NIR baseline-corrected water absorbances was observed for wet masses containing MCC. This was at the region of optimal water amount for granulation according to the torque results. In the case of anhydrous theophylline, the slope of baseline-corrected water absorbance values increased at the same water amount as the impeller torque started to increase. The hydrate formation of theophylline during granulation was observed as a slight decrease in the impeller torque. In addition, the hydrate formation during granulation affected the granulation liquid requirement. The liquid requirement was different for monohydrate formed during granulation compared to one formed in high relative humidity before the granulation. The results suggest that NIR spectroscopy may be applicable to process monitoring of wet granulation, also in cases where monitoring of impeller torque is difficult to apply.     

Mechanoradical-Induced Degradation in a Pharmaceutical Blend during High-Shear Processing

Mechanically generated radicals were shown to affect short-term stability of a model pharmaceutical formulation during high-shear processing. A formulation containing an oxidatively sensitive drug, either amorphous or crystalline, and a polymeric excipient was high-shear mixed and the resulting short-term degradation was determined with HPLC. High-shear mixing of the excipients was also carried out before drug addition to isolate effects on excipients versus those directly on the drug. Short-term drug stability was found to be strongly dependent on the amount of shear added to excipients prior to drug addition, regardless of morphology. A mechanism for the observed degradation based on mechanically generated radicals from microcrystalline cellulose is proposed. These results indicate that excipient high-shear exposure needs to be considered in regards to drug stability.     

Mechanoradical-induced degradation in a pharmaceutical blend during high-shear processing

Mechanically generated radicals were shown to affect short-term stability of a model pharmaceutical formulation during high-shear processing. A formulation containing an oxidatively sensitive drug, either amorphous or crystalline, and a polymeric excipient was high-shear mixed and the resulting short-term degradation was determined with HPLC. High-shear mixing of the excipients was also carried out before drug addition to isolate effects on excipients versus those directly on the drug. Short-term drug stability was found to be strongly dependent on the amount of shear added to excipients prior to drug addition, regardless of morphology. A mechanism for the observed degradation based on mechanically generated radicals from microcrystalline cellulose is proposed. These results indicate that excipient high-shear exposure needs to be considered in regards to drug stability.     

Real‐Time Monitoring of Changes of Adsorbed and Crystalline Water Contents in Tablet Formulation Powder Containing Theophylline Anhydrate at Various Temperatures During Agitated Granulation by Near‐Infrared Spectroscopy

Real‐time monitoring of adsorbed water content (FW) and hydrate formation of theophylline anhydrate (THA) in tablet formulation during agitated granulation was investigated by near‐infrared (NIR) spectroscopy. As the wet‐granulation process of THA tablet formulation involves change in pseudo‐polymorphs between THA and theophylline monohydrate (THM), the pharmaceutical properties of THA tablet depend on the degree of hydration during granulation. After mixing of the powder materials (4 g) containing THA, and excipients and the addition of 600 μL of binding water, the powder was kneaded at 27°C, 40°C, and 50°C and then dried. The mixing, granulating, and drying processes were monitored using NIR. The calibration models to predict THM and total water contents during granulation in THA tablet formulation were obtained by partial least‐squares regression. The FW in the formulation was determined by subtracting THM from the water content. The results of the THA formulation powder bed during granulation by NIR monitoring indicated that the transformation pathway of the THA powder was THA ⇒ THM ⇒ THA at 27°C and 40°C, but that at 50°C was THA ⇒ THA ⇒ THA. The pharmaceutical properties, such as tablet porosity, hardness, tablet disintegration time, and dissolution rate of the final THA tablet products, were affected by the degree of crystalline transformation during granulation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2924–2936, 2014     

Novel identification of pseudopolymorphic changes of theophylline during wet granulation using near infrared spectroscopy

The purpose of this study was to demonstrate the efficiency of near infrared (NIR) spectroscopy in studying the pseudopolymorphic changes and the state of water during the wet granulation process. Anhydrous theophylline was granulated in a planetary mixer using water as granulation liquid. NIR spectra and differential scanning calorimetric (DSC) and wide-angle X-ray scattering (WAXS) patterns of theophylline granules, anhydrous theophylline, and theophylline monohydrate were measured. At a low level of granulation liquid (0.3 mol of water per mole of anhydrous theophylline), water absorption maxima in the NIR region occurred first at around 1475 and 1970 nm. These absorption maxima were identical to those of theophylline monohydrate. At higher levels of granulation liquid (1.3-2.7 mol of water per mole of anhydrous theophylline), the increasing absorption maxima occurred at 1410 and 1905 nm due to OH vibrations of free water molecules. X-ray diffraction patterns confirmed the transformation of anhydrous theophylline to theophylline monohydrate during wet granulation. NIR spectroscopy was able to detect different states of water molecules during the wet granulation process faster and in a more flexible manner than conventional methods.     

Investigation of excipient type and level on drug release from controlled release tablets containing HPMC

The purpose of this study was to investigate the influence of excipient type and level on the release of alprazolam formulated in controlled release matrix tablets containing hydroxypropyl methylcellulose (HPMC). Each tablet formulation contained alprazolam, HPMC (Methocel K4MP), excipients, and magnesium stearate. The soluble excipients investigated were lactose monohydrate, sucrose, and dextrose, and the insoluble excipients included dicalcium phosphate dihydrate, dicalcium phosphate anhydrous, and calcium sulfate dihydrate. The similarity factor (f2 factor) was used to compare the dissolution profile of each formulation. The insoluble excipients, especially dicalcium phosphate dihydrate, caused the drug to be released at a slower rate and to a lesser extent than the soluble excipients. Soluble excipients created a more permeable hydrated gel layer for drug release, increased the porosity resulting in faster diffusion of drug, and increased the rate of tablet erosion. Use of binary mixtures of lactose monohydrate and dicalcium phosphate dihydrate produced release profiles of intermediate duration. Rapid drug dissolution was obtained when only 9.1% w/w of lactose monohydrate was present in the tablet formulation. Only when the dicalcium phosphate dihydrate level was sufficiently high (36.5% w/w) was the release rate and extent decreased. It was demonstrated that the type and level of excipient influenced the rate and extent of drug release from controlled release tablets containing HPMC. The release mechanism of alprazolam from each tablet formulation was described by either the Hixson-Crowell cube root kinetics equation or Peppas's equation. However, the different excipient types investigated did not influence the release mechanism of alprazolam from the final tablets.     

Drug hydrate systems and dehydration processes studied by terahertz pulsed spectroscopy

Terahertz pulsed spectroscopy was used to distinguish between different hydrate systems. In the example of four pharmaceutical materials lactose, carbamazepine, piroxicam and theophylline it was demonstrated that all different hydrate and anhydrate forms exhibit distinct spectra in the far infrared. Furthermore the dehydration of theophylline monohydrate was characterised in situ. Here, a phase transition from the monohydrate to the anhydrous form was observed, followed by evaporation of the hydrate water in a second step. The rotational spectrum of water vapour is very characteristic in the far infrared and can easily be discerned from the terahertz spectrum of the solid state form.     

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.     

Hydrate formation during wet granulation studied by spectroscopic methods and multivariate analysis

Purpose. The aim was to follow hydrate formation of two structurally related drugs, theophylline and caffeine, during wet granulation using fast and nondestructive spectroscopic methods. Methods. Anhydrous theophylline and caffeine were granulated with purified water. Charge-coupled device (CCD) Raman spectroscopy was compared with near-infrared spectroscopy (NIR) in following hydrate formation of drugs during wet granulation (off-line). To perform an at-line process analysis, the effect of water addition was monitored by NIR spectroscopy and principal components analysis (PCA). The changes in the crystal arrangements were verified by using X-ray powder diffraction (XRPD). Results. Hydrate formation of theophylline and caffeine could be followed by CCD Raman spectroscopy. The NIR and Raman spectroscopic results were consistent with each other. NIR revealed the state of water, and Raman spectroscopy gave information related to the drug molecule itself. The XRPD confirmed the spectroscopic results. PCA with three principal components explained 99.9of the spectral variation in the second derivative NIR spectra. Conclusions. Both CCD Raman and NIR spectroscopic methods can be applied to monitoring of hydrate formation processes. However, NIR is more suitable for monitoring solid-water interactions.     

Investigating the Use of Polymeric Binders in Twin Screw Melt Granulation Process for Improving Compactibility of Drugs

Traditionally, the melt granulation for pharmaceutical products was performed at low temperature (<90°C) with high-shear granulators using low-melting waxy binders, and tablets produced using such granules were not amenable to large-scale manufacturing. The situation has changed in recent years by the use of twin screw extruder where the processing temperature could be increased to as high as 180°C and polymers with high T_g could be used as binders. In this study, different polymeric binders were screened for their suitability in improving compactibility of 2 drugs, metformin hydrochloride and acetaminophen, by twin screw melt granulation. Processing temperatures for the 2 drugs were set at 180°C and 130°C, respectively. Screw configuration, screw speed, and feed rate were optimized such that all polymeric binders used produced granules. Several hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and methacrylate-based polymers, including Klucel^® EXF, Eudragit^® EPO, and Soluplus^®, demonstrated good tablet tensile strength (>2 MPa) when granules were produced using only 10% wt/wt polymer concentration. Certain polymers provided acceptable compactibility even at 5% wt/wt. Thus, twin screw melt granulation process may be used with different polymers at a wide range of temperature. Due to low excipient concentration, this granulation method is especially suitable for high-dose tablets.     

Kinetics Study of Cocrystal Formation Between Indomethacin and Saccharin Using High-Shear Granulation With In Situ Raman Spectroscopy

Pharmaceutical manufacturing processes are necessary to make solid dosage form even in cocrystal formation. In an effort to reduce the number of unit operations, high-shear wet granulation with cocrystallization system was proposed. In the present study, indomethacin-saccharin was chosen as a model compound, and the cocrystal formation kinetics was investigated during the consistent process. The role of each initial indomethacin crystal state (γ-form, α-form, or amorphous) for the kinetics was explored using in situ Raman spectroscopy with multivariate curve resolution by alternating least-squares analysis as a chemometrics. Obtained granules were characterized by X-ray diffraction and tablet dissolution testing. The Raman peaks assigned to indomethacin-saccharin cocrystal were increased with granulation when ethanol was used as a binding solvent. In addition, the reaction kinetics of run samples which had different indomethacin forms was distinguished by best fitting using Avrami–Erofeev or Ginstling–Brounshtein model. The kinetic variance depended on the initial thermodynamic state of indomethacin because they had a different crystallization mechanism for the cocrystal. The scalable and feasible granulation method is required in the pharmaceutical industry.     

Role of excipients on solid-state properties of piroxicam during processing

There is a need for an improved process understanding of solid dosage pharmaceuticals. In the present study, Raman spectroscopy together with partial least squares (PLS) regression was used to monitor the solid-state composition of piroxicam during processing in the presence of excipients. It was found that including variable selection in PLS regression offers improved quantitative models in terms of predictive performance, easier interpretation of results and reduced experimental workload relative to full-spectrum PLS regression. By means of the applied interval PLS (iPLS) regression model, it was observed that excipients with high water-absorbing potential (microcrystalline cellulose and hydroxypropyl cellulose) and a water-activity-reducing solvent (ethanol) delayed the onset of monohydrate formation during processing in aqueous environments. An alkalizing excipient (sodium bicarbonate) decreased the onset time of monohydrate formation during wet granulation and decreased the dehydration rate during a drying operation. In this study it is demonstrated that the physical stability of hydrate-anhydrate systems in process environments is complicated by a multitude of factors on both macroscopic level and molecular level, and that variable selection for PLS regression is a valuable tool for screening the effects of excipients on the solid-state properties of pharmaceuticals.     

Water Sorption Induced Transformations in Crystalline Solid Surfaces: Characterization by Atomic Force Microscopy

The effect of water sorption on the mobility of molecules on the surface of a crystalline anhydrous solid was investigated to understand the mechanism of its transformation to the corresponding hydrate. Theophylline was chosen as the model compound. The transition water activity for anhydrate to hydrate transformation, RH_T, and the deliquescence RH, RH₀, was determined to be 62% and 99%, respectively (25°C). Atomic force microscopy (AFM) was used to study the surface changes of theophylline above and below the transition water activity. Contact-mode AFM showed that the jump-to-contact distance increased appreciably above RH_T, suggesting formation of solution on the surface. At RH_T < RH < RH₀, using dynamic (AC/“tapping” mode) AFM, the movements of surface steps were visualized. These results from AFM indicated that, below RH₀, the formation of a thin solution film significantly increased surface mobility. Furthermore, when the anhydrate crystal surface was seeded with the hydrate, the propagation of a new hydrate phase was observed by polarized light microscopy. In conclusion, atomic force microscopy provided direct evidence that the phase transformation of anhydrous theophylline to theophylline monohydrate in the solid-state is mediated by a surface solution as a result of water adsorption. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4032–4041, 2010