Phase transformations of amlodipine besylate solid forms.

Hydrate formation and dehydration phenomena are frequently encountered phase transformations during manufacturing and storage of the drug products. It is essential to understand, monitor, and control these transformations to ensure that the quality attributes of the drug product are not affected. In this work, phase transformations of the solid forms of amlodipine besylate (AMB) were studied using Raman and near-infrared (NIR) spectroscopy.

Stabilization of liposomes during drying.

Introduction: During the past 40 years, liposomes have been investigated intensively as drug carriers for anticancer drugs and as the adjuvant components of vaccines, for example. In this context, the development of dry formulations of liposomes is important to ensure a more stable drug product and to avoid the use of the 'cold chain' during distribution.

Areas Covered: This review provides an overview of the technologies commonly used for the drying of liposomal formulations and the significance of formulation and processing parameters for the drying process.

Quality by design approach in the optimization of the spray-drying process.

Context/objective: The aim of this study was to illustrate the influence of the processing parameters, inlet temperature, atomization air flow rate and feed flow rate, on critical quality attributes of spray-dried powders using design of experiments (DoE).

Methods: Spray-dried powders were characterized by laser diffraction, X-ray powder diffraction (XRPD) and near-infrared spectroscopy (NIR). Multivariate analysis of two different experimental designs was performed to elucidate the optimal process conditions.

Rapid solid-state analysis of freeze-dried protein formulations using NIR and Raman spectroscopies.

Noninvasive near-infrared (NIR) and Raman spectroscopies were applied to provide a fast and efficient insight into the formation of different mannitol solid forms occurring in freeze-dried formulations. Multivariate data analysis clearly showed the formation of δ-mannitol in the presence of protein, whereas β-mannitol was observed in the absence of protein.The multivariate analysis of the NIR spectra also gave an indication for the formation of mannitol hemihydrate in the absence of protein.

Assessment of crystalline disorder in cryo-milled samples of indomethacin using atomic pair-wise distribution functions.

The aim of this study was to investigate the usefulness of the atomic pair-wise distribution function (PDF) to detect the extension of disorder/amorphousness induced into a crystalline drug using a cryo-milling technique, and to determine the optimal milling times to achieve amorphisation. The PDF analysis was performed on samples of indomethacin obtained by cryogenic ball milling (cryo-milling) for different periods of time. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), polarised light microscopy (PLM) and solid state nuclear magnetic resonances (ss-NMR) were also used to analyse the cryo-milled samples.

Building the quality into pellet manufacturing environment--feasibility study and validation of an in-line quantitative near infrared (NIR) method.

The present study focuses on the implementation of an in-line quantitative near infrared (NIR) spectroscopic method for determining the active content of pharmaceutical pellets. The first aim was to non-invasively interface a dispersive NIR spectrometer with four realistic particle streams existing in the pellets manufacturing environment. Regardless of the particle stream characteristics investigated, NIR together with Principal Component Analysis (PCA) was able to classify the samples according to their active content.

Bergen Burnout Inventory: reliability and validity among Finnish and Estonian managers.

Objectives: This study introduces a short measure for burnout (the Bergen Burnout Inventory, BBI) and examines its validity and reliability among managers in Finland and Estonia by means of confirmatory factor analysis. Burnout comprises three dimensions: (1) exhaustion at work (emotional component), (2) cynicism toward the meaning of work (cognitive component), and (3) the sense of inadequacy at work (behavioral component).

Methods: A total of 742 young Finnish managers and 414 Estonian managers responded to burnout (BBI) and effort-reward imbalance (ERI) scales.

The influence of thermal history on the physical behavior of poly(ethylene glycol) (PEG).

Objectives: To investigate the influence of thermal history on the physical behavior of poly(ethylene glycol) (PEG), commonly used as a pharmaceutical excipient.

Materials And Methods: Rheological investigations together with SEM imaging and solid state analysis by XRPD and DSC were used to characterize PEG as starting material, as well as PEG:lactose monohydrate granules. For granulation experiments PEG 6000 was used and for further investigations of physicochemical properties, three M(w) of PEG (3000-10000) with different thermal histories obtained by melting the PEG followed by solidification with specific cooling rates.

Factors affecting crystallization of hydrates.

Objectives: To provide a comprehensive understanding of the competing thermodynamic and kinetic factors governing the crystallization of various hydrate systems. The ultimate goal is to utilize this understanding to improve the control over the unit operations involving hydrate formation, as well as to optimize the bioavailability of a given drug product.

Key Findings: The thermodynamic and kinetic factors that govern hydrate crystallization are introduced and the current status of the endeavour to gain a mechanistic understanding of the phenomena that occur during the crystallization of different hydrate systems is discussed.

Influence of temperature on solvent-mediated anhydrate-to-hydrate transformation kinetics.

Purpose: To achieve an in-depth understanding of the underlying mechanism of the acceleration or deceleration effect of temperature on solvent-mediated anhydrate-to-hydrate phase transformation.

Methods: The effect of temperature on the phase transformation rate and onset time of two model compounds was investigated using in situ Raman spectroscopy. The thermodynamic driving force of the phase transformation (e.

Towards a robust water content determination of freeze-dried samples by near-infrared spectroscopy.

The possibility for determination of the water content in pharmaceutical samples by near-infrared (NIR) spectroscopy has been more widely investigated in the past few years. However, many studies claim that changes in sample composition will require the establishment of a new method. The aim of this study was several fold: firstly to investigate validation aspects of water content determination in samples with varying composition and furthermore to see if a model based solely on freeze-dried mannitol-sucrose mixtures can be established that will be able to predict water contents for samples containing proteins, excipients or having a lower density of freeze-dried solids.

Integrated approach to study the dehydration kinetics of nitrofurantoin monohydrate.

There is a need for thorough knowledge of solid-state transformations in order to implement quality by design (QbD) methodology in drug development. The present study was aimed at gaining a mechanistic understanding of the dehydration of nitrofurantoin monohydrate II (NF-MH). The dehydration was studied using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), hot-stage microscopy (HSM), and variable temperature X-ray powder diffraction (VT-XRPD).

Towards effective solid form screening.

Solid form screening is commonly performed using solvent-based crystallizations. However, less attention is paid to the role of secondary manufacturing, during which process-induced transformations of the active pharmaceutical ingredient (API) may occur, and potentially a new solid form may be discovered. In this study a new approach for effective solid form screening is presented.

Building quality into a coating process.

An effective approach towards optimal development strategy is to use the quality by design principle. However, this approach can first be implemented when possible risks impacting critical quality attributes are defined and interactions between those are fully understood. The objective of this study was to identify critical variables that affect the final modified release product performance using a risk management approach with supporting statistical tool.

An insight into water of crystallization during processing using vibrational spectroscopy.

Many organic molecules used as drugs can incorporate water into their crystal lattice. These compounds are also prone to processing-induced transformations (PITs) because processing often exposes the compounds to moisture, heat and mechanical stress. The aim of this review is to provide an overview of the possibilities for following and understanding hydrate/anhydrate transformations using vibrational spectroscopy (mid-infrared, near-infrared, Raman and terahertz).

Classification of lyophilised mixtures using multivariate analysis of NIR spectra.

Excipient selection is critically affecting the processing and the stability of a lyophilised product. Near infra-red (NIR) spectroscopy was applied to investigate freeze-dried samples containing varying ratios of the commonly used excipients mannitol and sucrose. Further variation in the formulation was achieved by adding NaCl, CaCl(2) and histidine and by exposing the samples to different conditions.

Crystallization of a polymorphic hydrate system.

Nitrofurantoin can form two monohydrates, which have the same chemical composition and molar ratio of water, but differ in the crystal arrangements. The two monohydrates (hydrates I and II) could be produced independently via evaporative crystallization, where supersaturation and solvent composition were both found to have an effect. Hydrate I showed much slower crystallization than hydrate II.

Enhanced dissolution rate and synchronized release of drugs in binary systems through formulation: Amorphous naproxen-cimetidine mixtures prepared by mechanical activation.

Naproxen, a non-steroidal anti-inflammatory drug (NSAID), is a biopharmaceutics classification system (BCS) class II drug whose bioavailability is rate-limited by its dissolution. Cimetidine is sometimes co-administered with naproxen for the treatment of NSAID-induced gastro-intestinal disorders. Hence, there is interest in the design of new formulations that offer (1) concomitant release of both drugs, and (2) an enhanced dissolution rate of naproxen.

Role of excipients in the quantification of water in lyophilised mixtures using NIR spectroscopy.

The ratio between mannitol and sucrose in a freeze-dried formulation has a major impact on the processing and the stability of a lyophilised product. The ratio of these common excipients influences a critical quality attribute of the system, namely the overall amount of water, due to the different nature of their water-solid interactions. For this experiment samples containing various ratios of mannitol and sucrose and several other additives were freeze-dried, stored under different conditions and measured by NIR.

Crystal morphology engineering of pharmaceutical solids: tabletting performance enhancement.

Crystal morphology engineering of a macrolide antibiotic, erythromycin A dihydrate, was investigated as a tool for tailoring tabletting performance of pharmaceutical solids. Crystal habit modification was induced by using a common pharmaceutical excipient, hydroxypropyl cellulose, as an additive during crystallization from solution. Observed morphology of the crystals was compared with the predicted Bravais-Friedel-Donnay-Harker morphology.

Structural characterisation and dehydration behaviour of siramesine hydrochloride.

In this study the crystal structures of siramesine hydrochloride anhydrate alpha-form and siramesine hydrochloride monohydrate were determined, and this structural information was used to explain the physicochemical properties of the two solid forms. In the crystal structure of the monohydrate, each water molecule is hydrogen bonded to two chloride ions, and thus the water is relatively strongly bound in the crystal. No apparent channels for dehydration were observed in the monohydrate structure, which could allow transmission of structural information during dehydration.

Effects of polymer additives on the crystallization of hydrates: a molecular-level modulation.

The purpose of this study is to elucidate the effects of polymer additives on the growth behavior and final internal structure of hydrate crystals. The polymers used were poly(ethylene) glycol (PEG), ethyl(hydroxyethyl) cellulose (EHEC) and hydroxylpropyl methylcellulose (HPMC). Rheological characterization of the polymer solutions was carried out.

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.

Near-infrared spectroscopy for cocrystal screening. A comparative study with Raman spectroscopy.

Near-infrared (NIR) spectroscopy is a well-established technique for solid-state analysis, providing fast, noninvasive measurements. The use of NIR spectroscopy for polymorph screening and the associated advantages have recently been demonstrated. The objective of this work was to evaluate the analytical potential of NIR spectroscopy for cocrystal screening using Raman spectroscopy as a comparative method.