Image Analysis Quantification of Sticking and Picking Events of Pharmaceutical Powders Compressed on a Rotary Tablet Press Simulator

Purpose

The aim of this work was to develop a quantification method based on image analysis, able to characterize sticking during pharmaceutical tableting. Relationship between image analysis features and relevant mechanical parameters recorded on an instrumented tablet press simulator were investigated.

Methods

Image analysis, based on gray levels co-occurrence matrices (GLCM), generated textural features of the tablet surface. The tableting simulator (Stylcam® 200R, Medelpharm), instrumented with force and displacement transducers, provided accurate records. The tablet defects and compaction process parameters were studied using three pharmaceutical powders (Fast-Flo® lactose, anhydrous Emcompress® and Avicel® PH200 microcrystalline cellulose), five compression pressures (60 to 250 MPa), five lubricating levels, and three types of punches (standard steel, amorphous hard carbon and anti-sticking punches).

Results

Texture parameters made it possible to quantify with precision tablets’ aspect. The selected parameter IC2 (Information on Correlation 2) plotted versus the ratio between the ejection shear stress (Esh) and the compression pressure (Cp) let appear a relevant knowledge space where it was possible to identify a normal and a degraded tableting mode. A positive link between those two parameters was shown.

Conclusion

Since the Esh/Cp ratio was related to image analysis results, it proved to be an interesting defect tag.     

Development of a Statistical Tolerance-Based Fluid Bed Drying Design Space

Introduction

The pharmaceutical industry has invested a substantial amount of resources in recent years to develop manufacturing systems that offer improved product quality while limiting costs. The US Food and Drug Administration (FDA) has encouraged the use of the guidelines put forth by the International Conference on Harmonization [ICH-Q8(R2)] that allow for operational flexibility within a validated design space to allow automated systems that incorporate real-time data management. Use of these systems requires substantial process understanding that is typically gained through appropriately developed design of experiments. Appropriate analyses of the data are required to optimize the understanding gained from experiments. Furthermore, these analyses must be combined with existing product specifications to set justifiable operating limits for the process.

Material and Methods

Granules containing gabapentin, and hydroxypropyl cellulose were prepared in a high-shear granulator and dried in a fluid bed processing system. The fluid bed dryer was outfitted with near infrared, pressure, temperature, and flow sensors, which were connected to a distributed control system that was used to exercise control of the system. The dried granules were blended with extragranular excipients and then compressed on a rotary tablet press. Designed experimental variations to processing were utilized at each of the manufacturing steps to produce a design space. The outputs of the design (quality attributes) that were considered in this work were the quantity of gabapentin lactam formed during processing, tablet crushing strength, final blend flow properties, and median particle size of dried granules.

Results

A tolerance-based design space was constructed for each of the quality attributes considered, and an overall design space was calculated based on the individual unit operations. The overall design space was a combination of process models and was calculated to include the uncertainty (variance) from each of the unit operations and measurements. A tolerance design space was calculated that reflects the probability that a given combination of processing parameters will produce critical quality attributes within specifications.     

Multivariate Image and Texture Analysis to Investigate the Erosion Mechanism of Film-coated Tablets: An Industrial Case Study

Introduction

The Quality by Design initiative requires the design space of a process to be based on metrics that are robust and reproducible, and not on qualitative ones that might be easily biased by human perception. Hence, the use of image analysis is attractive for practical industrial applications where the quality assessment is still typically performed by a panel of trained experts.

Methods

The use of multivariate image and texture analysis is proposed in this study to quantitatively characterize the elegance of film-coated tablets. Four unsupervised metrics are developed to quantify both the color uniformity of tablet faces/bands and the surface erosion. To develop robust statistics, more than 7,000 tablets coated in nine different pilot-scale batches are considered. Latent variable modeling is used to regress the measured elegance against coating operating conditions to investigate the driving forces acting on the system and guide pharmaceutical manufacturing, consistently with the Quality by Design framework.

Results

The model allows one to successfully investigate the causes leading to tablet erosion. Additionally, it is shown that the model space can be effectively used as a monitoring chart of the overall batch elegance in terms of color uniformity and surface erosion, since the batches are found to rank according to the surface roughness of the manufactured tablets.

Conclusions

Image analysis has been shown to be an effective process analytical technology for the development of the design space of a film-coating process, where quality assessment on the final product is traditionally based on the judgment of panel of trained experts.     

Non-destructive Determination of Disintegration Time and Dissolution in Immediate Release Tablets by Terahertz Transmission Measurements

Purpose

The aim of this study was to establish the suitability of terahertz (THz) transmission measurements to accurately measure and predict the critical quality attributes of disintegration time and the amount of active pharmaceutical ingredient (API) dissolved after 15, 20 and 25 min for commercial tablets processed at production scale.

Methods

Samples of 18 batches of biconvex tablets from a production-scale design of experiments study into exploring the design space of a commercial tablet manufacturing process were used. The tablet production involved the process steps of high-shear wet granulation, fluid-bed drying and subsequent compaction. The 18 batches were produced using a 4 factor split plot design to study the effects of process changes on the disintegration time. Non-destructive and contactless terahertz transmission measurements of the whole tablets without prior sample preparation were performed to measure the effective refractive index and absorption coefficient of 6 tablets per batch.

Results

The disintegration time (R ²?=?0.86) and API dissolved after 15 min (R ²?=?0.96) linearly correlates with the effective refractive index, n _eff, measured at terahertz frequencies. In contrast, no such correlation could be established from conventional hardness measurements. The magnitude of n _eff represents the optical density of the sample and thus it reflects both changes in tablet porosity as well as granule density. For the absorption coefficient, α _eff, we observed a better correlation with dissolution after 20 min (R ²?=?0.96) and a weaker correlation with disintegration (R ²?=?0.83) compared to n _eff.

Conclusion

The measurements of n _eff and α _eff provide promising predictors for the disintegration and dissolution time of tablets. The high penetration power of terahertz radiation makes it possible to sample a significant volume proportion of a tablet without any prior sample preparation. Together with the short measurement time (seconds), the potential to measure content uniformity and the fact that the method requires no chemometric models this technology shows clear promise to be established as a process analyser to non-destructively predict critical quality attributes of tablets.

     

Optimization of Chronomodulated Delivery System Coated with a Blend of Ethyl Cellulose and Eudragit L100 by Central Composite Design: In Vitro and In Vivo Evaluation

Introduction

In this study, we present the development of a chronomodulated delivery system consisting of a fast-swelling tablet core containing montelukast sodium coated with a blend of different ratios of ethyl cellulose (gastrointestinal tract (GIT)-insoluble polymer) and Eudragit L100 (enteric polymer). Montelukast sodium is a leukotriene receptor antagonist commonly prescribed for patients of asthma and allergic rhinitis. Asthma and allergic rhinitis share a common core pathophysiology and have almost similar temporal pattern in their occurrence or exacerbation of their respective symptoms, suggesting a role for chronotherapy.

Methods

The developed formulation was optimized statistically using central composite design to achieve desired release profile. The coated tablets were studied for water uptake, bursting time, and in vitro release study.

Results

The bursting time (lag time) of coated tablet was affected by the pH of buffer, molarity of ions, and concentration of different types of surfactant in dissolution media. With increasing percentage of Eudragit L100 in coating composition, the lag time decreased and release rates significantly increased—could be attributed due to increase in water uptake and polymer leaching. As expected, with increasing coating level, lag time increased and release rate decreased due to the increased diffusion pathways. In vivo study revealed comparative pharmacokinetic profiles of core tablets and pulsatile release tablets (PRTs); however, T _max of 2 h for core tablets and 6 h for PRTs were observed.

Conclusion

Thus, designed PRTs were found to be suitable in treating episodic attack of asthma in early morning and associated allergic rhinitis.     

The Impact of Granule Density on Tabletting and Pharmaceutical Product Performance

Purpose

The impact of granule densification in high-shear wet granulation on tabletting and product performance was investigated, at pharmaceutical production scale. Product performance criteria need to be balanced with the need to deliver manufacturability criteria to assure robust industrial scale tablet manufacturing processes. A Quality by Design approach was used to determine in-process control specifications for tabletting, propose a design space for disintegration and dissolution, and to understand the permitted operating limits and required controls for an industrial tabletting process.

Methods

Granules of varying density (filling density) were made by varying water amount added, spray rate, and wet massing time in a design of experiment (DoE) approach. Granules were compressed into tablets to a range of thicknesses to obtain tablets of varying breaking force. Disintegration and dissolution performance was evaluated for the tablets made. The impact of granule filling density on tabletting was rationalised with compressibility, tabletability and compactibility.

Results

Tabletting and product performance criteria provided competing requirements for porosity. An increase in granule filling density impacted tabletability and compactability and limited the ability to achieve tablets of adequate mechanical strength. An increase in tablet solid fraction (decreased porosity) impacted disintegration and dissolution. An attribute-based design space for disintegration and dissolution was specified to achieve both product performance and manufacturability.

Conclusion

The method of granulation and resulting granule filling density is a key design consideration to achieve both product performance and manufacturability required for modern industrial scale pharmaceutical product manufacture and distribution.

     

Microstructure of Tablet—Pharmaceutical Significance,Assessment, and Engineering

Purpose

To summarize the microstructure – property relationship of pharmaceutical tablets and approaches to improve tablet properties through tablet microstructure engineering.

Method

The main topics reviewed here include: 1) influence of material properties and manufacturing process parameters on the evolution of tablet microstructure; 2) impact of tablet structure on tablet properties; 3) assessment of tablet microstructure; 4) development and engineering of tablet microstructure.

Results

Microstructure plays a decisive role on important pharmaceutical properties of a tablet, such as disintegration, drug release, and mechanical strength. Useful information on mechanical properties of a powder can be obtained from analyzing tablet porosity—pressure data. When helium pycnometry fails to accurately measure true density of a water-containing powder, non-linear regression of tablet density—pressure data is a useful alternative method. A component that is more uniformly distributed in a tablet generally exerts more influence on the overall tablet properties.

Conclusion

During formulation development, it is highly recommended to examine the relationship between any property of interest and tablet porosity when possible. Tablet microstructure can be engineered by judicious selection of formulation composition, including the use of the optimum solid form of the drug and appropriate type and amount of excipients, and controlling manufacturing process.

     

A critical Examination of the Phenomenon of Bonding Area - Bonding Strength Interplay in Powder Tableting

Purpose

Although the bonding area (BA) and bonding strength (BS) interplay is used to explain complex tableting behaviors, it has never been experimentally proven. The purpose of this study is to unambiguously establish the distinct contributions of each by decoupling the contributions from BA and BS.

Methods

To modulate BA, a Soluplus® powder was compressed into tablets at different temperatures and then broken following equilibration at 25°C. To modulate BS, tablets were equilibrated at different temperatures. To simultaneously modulate BA and BS, both powder compression and tablet breaking test were carried out at different temperatures.

Results

Lower tablet tensile strength is observed when the powder is compressed at a lower temperature but broken at 25°C. This is consistent with the increased resistance to polymer deformation at lower temperatures. When equilibrated at different temperatures, the tensile strength of tablets prepared under identical conditions increases with decreasing storage temperature, indicating that BS is higher at a lower temperature. When powder compression and tablet breaking are carried out at the same temperature, the profile with a maximum tensile strength at 4°C is observed due to the BA-BS interplay.

Conclusion

By systematically varying temperature during tablet compression and breaking, we have experimentally demonstrated the phenomenon of BA-BS interplay in tableting.

     

Understanding the Effect of Environmental History on Bilayer Tablet Interfacial Shear Strength

Purpose

To understand the effect of post production environmental conditions on the interfacial strength of bilayer tablets.

Methods

Bilayer tablets of microcrystalline cellulose/dicalcium phosphate were exposed to several humidity conditions higher/lower than production conditions and tested in shear to assess interfacial strength. Specific failure mechanisms were observed using x-ray microtomography and scanning electron microscopy.

Results

Transients in moisture diffusion of bilayer tablets with significant differential moisture absorption characteristics are responsible for the reduction of strength in both high and low moisture environments. X-ray microtomography and SEM experiments have shown that two different mechanisms of interfacial crack formation are present. For low moisture exposure, interfacial cracks close to the surface were produced, whereas at high moisture conditions, internal interfacial cracks were created. In both cases the fracture modes are consistent with the tensile stresses that develop locally due to the volumetric strains induced by moisture absorption.

Conclusions

The insight gained from this work will be useful for material selection and packaging of bilayer tablet systems. While additional work is needed to develop specific guidelines for the optimization of bilayer strength, the results presented here provide a rational basis upon which such work can be conducted.     

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.     

Engineering of an Inhalable DDA/TDB Liposomal Adjuvant: A Quality-by-Design Approach Towards Optimization of the Spray Drying Process

Purpose

The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6′-dibehenate (TDB).

Methods

A quality by design (QbD) approach was applied to identify and link critical process parameters (CPPs) of the spray drying process to critical quality attributes (CQAs) using risk assessment and design of experiments (DoE), followed by identification of an optimal operating space (OOS). A central composite face-centered design was carried out followed by multiple linear regression analysis.

Results

Four CQAs were identified; the mass median aerodynamic diameter (MMAD), the liposome stability (size) during processing, the moisture content and the yield. Five CPPs (drying airflow, feed flow rate, feedstock concentration, atomizing airflow and outlet temperature) were identified and tested in a systematic way. The MMAD and the yield were successfully modeled. For the liposome size stability, the ratio between the size after and before spray drying was modeled successfully. The model for the residual moisture content was poor, although, the moisture content was below 3% in the entire design space. Finally, the OOS was drafted from the constructed models for the spray drying of trehalose stabilized DDA/TDB liposomes.

Conclusions

The QbD approach for the spray drying process should include a careful consideration of the quality target product profile. This approach implementing risk assessment and DoE was successfully applied to optimize the spray drying of an inhalable DDA/TDB liposomal adjuvant designed for pulmonary vaccination.

Functionalized Calcium Carbonate as a Novel Pharmaceutical Excipient for the Preparation of Orally Dispersible Tablets

Purpose

To overcome the limitation of insufficient hardness during the production of rapidly disintegrating orally dispersible tablets (ODTs). Furthermore, we investigated the properties and usefulness of functionalized calcium carbonate (FCC) as a new pharmaceutical excipient for the production of ODTs.

Methods

A highly sensitive tensiometer-based method was developed to measure kinetics of weight loss during tablet disintegration. With this method we were able to determine the residence time of tablets placed on a basket immersed into a test medium. The shapes of tensiometer plots allowed us to categorize substances into four different types of disintegration.

Results

At the same volume and hardness, the tablet formulations with FCC showed a significantly higher porosity (over 60%) than all other formulations. Residence time depended mainly on the tablet composition rather than on porosity. When combined with disintegrants, FCC formulations exhibited favorable disintegration properties, comparable to those of the marketed drug risperidone oro (disintegration time ca. 10 s).

Conclusions

Oral dosage forms - based on the new pharmaceutical excipient FCC - can be designed to have a short disintegration time combined with good mechanical strength. Due to these properties, FCC can be used for the preparation of ODTs.     

Adding a Factor in the Course of a Design Space Characterization

Introduction

An early decision on the design space of a pharmaceutical could imply that some process parameter is to be held fixed during production. Therefore, the effect of such a parameter is not studied in the exploration of the design space with statistically designed experiments. Later decisions may necessitate a changed setting of the parameter.

Purpose and Methods

In this paper we discuss a statistical design strategy that permit inclusion of a new parameter in the course of a design space characterization and the risks one could run in adopting the strategy. The main tool used is computer simulation based on an initial design of 48 runs and 12 factors, which may or may not have been completed before introduction of a 13d factor.

Results and Conclusions

If the original statistical design has a particular structure, new settings of the parameter can be introduced halfway the originally intended experimentation without having to start a completely new exploration of the design space.     

In-line Size Monitoring of a Twin Screw Granulation Process Using High-Speed Imaging

Purpose

This study aimed to evaluate the feasibility of implementing a 3D high-speed imaging camera for in-line monitoring of a continuous wet granulation process and its potential for real-time process control.

Methods

The Eyecon^TM camera was used for monitoring a twin screw granulated-placebo formulation composed of lactose (73.5 %), microcrystalline cellulose (20 %), hydroxypropylmethyl cellulose (5 %), and croscarmellose sodium (1.5 %). Water was used as the granulating liquid at liquid-to-solid (L/S) ratios from 0.15 to 0.35 at 0.05 increments. The lactose particle size was varied using three grades of lactose: pharmatose 200 M, impalpable, and SuperTab 30GR. The process was perturbed by changing the L/S ratio, while monitoring the process using the camera. A Shewhart control chart was constructed using control limits obtained under steady-state conditions. Statistical process control tools were used to assess the implications of choosing different quality characteristics on the detectability of process shifts.

Results

The camera showed sensitivity to variation in process parameters, which was evident in the calculated granule size and particle count. Larger particles had strong leverage on the converted volume distribution, which significantly affected the magnitude of variability in the statistics of particle diameters. It was shown that particle count and d ₁₀ were more sensitive to process shifts than d ₅₀ and d ₉₀.

Conclusions

The sensitivity of the high-speed camera, coupled with image analysis, to process perturbations and the variety of generated characteristics of particle attributes demonstrate the potential of this technique for continuous process monitoring and control.     

Linear Delivery of Verapamil via Nanofibrous Sheet-Based System

Purpose

To achieve linear delivery of a highly water-soluble oral drug, verapamil, with a nanofibrous sheet-based system.

Methods

The nanofibrous sheets made of poly (lactic-co-glycolic acid) were used as a diffusion barrier to cap a tablet containing verapamil. For controlled drug delivery, we varied the sheet thickness to 20???m, 50???m and 80???m to give the capped drug tablets, 20CT, 50CT and 80CT, respectively.

Results

Drug release was more sustained as the sheet thickness increased. Thus, the periods for almost complete drug release could be extended up to 14?h with the 80???m-thick sheets. As we assessed the linear least square fits to the in vitro drug release data from the capped tablets, 20CT and 50CT showed a fairly good correlation with linear release. The periods of linear release were 6?h and 8?h for 20CT and 50CT, respectively, both releasing more than 85% drug during this period.

Conclusion

We conclude that a drug tablet capped with nanofibrous sheets is a promising system for linear delivery of a highly water-soluble oral drug.     

Potential of Raman Spectroscopy for Evaluating Crushing Strength of Tablets

Introduction  

This study evaluates the sensitivity of Raman spectroscopy to changes in physical attributes of the compacted pharmaceutical formulations prepared with lactose monohydrate (49 wt.%), microcrystalline cellulose (49 wt.%), silicone dioxide (1 wt.%), and magnesium stearate (1 wt.%). The tablets made with raw powder were subjected to two iterative dry granulation cycles, i.e., tablet crushing, sieving, and re-tableting. Different compaction forces were applied during tableting. Small- and wide-angle X-ray scattering was used to study physical changes of the granulates and their respective compacts.     

Absorption of different oral dosage forms of oxycodone in the elderly: a cross-over clinical trial in patients undergoing cystoscopy

Purpose

To characterize the pharmacokinetics (PK) of oxycodone following intravenous injection and administration of three oral dosage forms (solution, capsule, and controlled-release tablet) in elderly patients (age 76–89?years) undergoing cystoscopy.

Methods

This was an open, randomized study with two sequences and two visits in 15 elderly patients. The patients were given intravenous injection (over 10?min) of 5?mg of oxycodone hydrochloride trihydrate. Oxycodone hydrochloride (5?mg in all forms) was orally administered as a solution, a capsule, and a controlled-release tablet. Venous blood samples were collected up to 17?h after oxycodone administration. Population PK parameters were calculated with NONMEM VI 2.0. For intravenous injection we calculated clearance, volume of distribution at steady state, and the half-life of elimination, and for oral dosage forms also the absolute bioavailability.

Results

Clearance of the intravenous injections was 28.9?L/h; the volume of distribution at steady state and the half-life of elimination were 186?L and 5.2?h, respectively. The absolute bioavailability of oxycodone was 59?% from oral solutions, 64?% from capsules, and 55?% from controlled-release tablets.

Conclusions

Our results indicate that, in the elderly, the bioavailability of the three different oral dosage forms of oxycodone is fairly similar.     

Formulation Design of Time-Controlled Release Formulation Containing Antidiabetic Drugs

Purpose

Type 2 diabetes mellitus (T2DM) is a silent killer disorder which is a public health challenge all over the world. The higher morbidity and mortality rate of T2DM hobble health care systems and the economy worldwide. Insulin resistance and relatively reduced insulin secretion are the main characteristics of T2DM. The present study was aimed to design and develop a bimodal release formulation of repaglinide and metformin hydrochloride to control the changes in blood sugar level according to daily routine and to maintaining it in an appropriate range using experimental design techniques.

Methods

The bilayer press-coated tablet showing time-controlled release was formulated using direct compression method by forming repaglinide immediate release layer and another of metformin hydrochloride as a time-controlled release layer. The 3² factorial design was applied for the press-coated layer of metformin hydrochloride by varying the concentration of polymers.

Results

Optimized composition was found to be shown the drug release of 62.44 % of repaglinide and above 98 % of that of metformin hydrochloride with a predesigned lag time. The patient-friendly formulation was found to be beneficial which mainly decreases dosing frequency, increases the therapeutic effect of both insulin-sensitizing drugs, and releases the drugs with a predetermined time pattern.

Conclusions

The work accomplished successfully developed a time-controlled, bilayer, bimodal release formulation for T2DM having immediate release of repaglinide and time-controlled release of metformin hydrochloride using press-coating technique. The formulation will increase patient compliance as compared to formulation containing individual drug available in the market.     

Subdivision of Tablets Containing Modified Delivery Technology: the Case of Orally Disintegrating Tablets

Purpose

Clinical practice suggests orally disintegrating tablets (ODTs) may be subdivided for dose adjustments, however there are no studies evaluating the effect of this practice in ODTs quality parameters. This work was therefore dedicated to elucidating the impact of the tablet subdivision on ten selected ODTs produced by different technologies.

Methods

Structural properties were assessed using weight; dimensions; image analysis; moisture content and porosimetry evaluations. Functional evaluations were also performed by disintegration and wetting assays. Tablets were evaluated just after subdivision and after an accelerated aging.

Results

Outcomes suggest the manufacturing method plays an important role in the suitability of ODTs for subdivision. While tablets containing granules immersed in a powdered matrix structure showed poor subdivision performance, with high weight variation and weight loss, tablets obtained by freeze-drying or direct compression of powder mixtures showed acceptable levels of these parameters and could be subdivided for immediate use. Aged tablets revealed structural and/or functional damages for all analyzed drug products, which includes softening of their matrices, water uptake and darkening, with loss of their disintegration and wetting capacities, which suggest inadequacy of ODTs subdivision for later use.

Conclusions

The results exposed in this study could be useful for the clinical decision on the subdivision of this tablets category.

     

Elucidation of Compression-Induced Surface Crystallization in Amorphous Tablets Using Sum Frequency Generation (SFG) Microscopy

Purpose

To investigate the effect of compression on the crystallization behavior in amorphous tablets using sum frequency generation (SFG) microscopy imaging and more established analytical methods.

Method

Tablets containing neat amorphous griseofulvin with/without excipients (silica, hydroxypropyl methylcellulose acetate succinate (HPMCAS), microcrystalline cellulose (MCC) and polyethylene glycol (PEG)) were prepared. They were analyzed upon preparation and storage using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM) and SFG microscopy.

Results

Compression-induced crystallization occurred predominantly on the surface of the neat amorphous griseofulvin tablets, with minimal crystallinity being detected in the core of the tablets. The presence of various types of excipients was not able to mitigate the compression-induced surface crystallization of the amorphous griseofulvin tablets. However, the excipients affected the crystallization rate of amorphous griseofulvin in the core of the tablet upon compression and storage.

Conclusions

SFG microscopy can be used in combination with ATR-FTIR spectroscopy and SEM to understand the crystallization behaviour of amorphous tablets upon compression and storage. When selecting excipients for amorphous formulations, it is important to consider the effect of the excipients on the physical stability of the amorphous formulations.