Jukka Rantanen

Solid form screening – A review

Solid form screening, the activity of generating and analysing different solid forms of an active pharmaceutical ingredient (API), has become an essential part of drug development. The multi-step screening process needs to be designed, performed and evaluated carefully, since the decisions made based on the screening may have consequences on the whole lifecycle of a pharmaceutical product. The selection of the form for development is made after solid form screening. The selection criteria include not only pharmaceutically relevant properties, such as therapeutic efficacy and processing characteristics, but also intellectual property (IP) issues. In this paper, basic principles of solid form screening are reviewed, including the methods used in experimental screening (generation, characterisation and analysis of solid forms, data mining tools, and high-throughput screening technologies) as well as basics of computational methods. Differences between solid form screening strategies of branded and generic pharmaceutical manufacturers are also discussed.

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. This study investigates the formation of amorphous binary systems with naproxen and cimetidine. The binary mixtures of all tested molar ratios were found to become amorphous upon co-milling for 60 min at 4 degrees C. In contrast, pure naproxen could not be transformed to the amorphous state by mechanical activation. The 1:1 sample was the most physically stable when stored for 33 days at 40 degrees C, even though it did not have the highest T(g) when compared to the 1:2 sample. The 1:1 sample was further stored for 186 days and remained amorphous under all conditions. Raman spectroscopy suggested a 1:1 solid-state interaction between the imidazole ring of cimetidine and the carboxylic acid moiety of naproxen in the co-milled amorphous sample. Thus, the stabilization of the amorphous binary system is dictated by molecular-level interactions rather than bulk-level phenomena. No recrystallization of either drug in the 1:1 co-milled sample was observed during dissolution testing, with naproxen and cimetidine having a four and two times higher intrinsic dissolution rate, respectively, compared to their crystalline counterparts. Further, the release of the two drugs could be synchronized using this formulation approach.

Raman spectroscopy for quantitative analysis of pharmaceutical solids.

Raman spectroscopy is experiencing a surge in interest in solid‐state pharmaceutical applications. It is rapid, non‐destructive, no sample preparation is required and measurements can be made in aqueous environments. It can be used for not only qualitative, but also quantitative, analysis. In this paper, the use of Raman spectroscopy for quantitative analysis of pharmaceutical solids is reviewed. The technique has been used for chemical and physical form analysis. Physical form analysis has involved quantification of polymorphism, hydrates, the amorphous form and, recently, protein conformation. Initially, simple powder systems were quantified, although this has since extended to complex pharmaceutical formulations, including tablets, capsules, microspheres and suspensions. Formulations have also been analysed through packaging. The characteristics of the technique make it ideal for process monitoring and it has been used to quantify changes in‐situ during processes such as wet granulation and batch crystallisation. The theoretical basis of quantitative Raman spectroscopy, common data analysis approaches, including multivariate analysis, and sources of error in quantitative analysis are also discussed.

On-line monitoring of moisture content in an instrumented fluidized bed granulator with a multi-channel NIR moisture sensor

The applicability of a near-infrared reflectance spectroscopic method was tested. The set-up used was constructed for the determination of water during different unit operations performed in a fluidized bed granulator. The granulation of three different formulations and the drying of one pellet formulation were investigated. The pellets were prepared by the continuous extrusion spheronisation technique. It proved possible to measure the moisture content of granules with a standard error of performance of 0.2%. The reference method used was based on the measurement of loss on drying (infrared dryer, wet basis). The applicability of the near-infrared method in pharmaceutical formulation and process development work was investigated using different liquid flow rates and drying end points. Combining the continuous measurement of moisture content and the product temperature measurement creates a novel tool for observing both the granule spraying and the drying phase. Different moisture profiles of the granules were clearly distinguished as well as the different drying end points.

The Future of Pharmaceutical Manufacturing Sciences

The entire pharmaceutical sector is in an urgent need of both innovative technological solutions and fundamental scientific work, enabling the production of highly engineered drug products. Commercial‐scale manufacturing of complex drug delivery systems (DDSs) using the existing technologies is challenging. This review covers important elements of manufacturing sciences, beginning with risk management strategies and design of experiments (DoE) techniques. Experimental techniques should, where possible, be supported by computational approaches. With that regard, state‐of‐art mechanistic process modeling techniques are described in detail. Implementation of materials science tools paves the way to molecular‐based processing of future DDSs. A snapshot of some of the existing tools is presented. Additionally, general engineering principles are discussed covering process measurement and process control solutions. Last part of the review addresses future manufacturing solutions, covering continuous processing and, specifically, hot‐melt processing and printing‐based technologies. Finally, challenges related to implementing these technologies as a part of future health care systems are discussed.

In-line moisture measurement during granulation with a four-wavelength near infrared sensor: an evaluation of particle size and binder effects.

Factors affecting in-line near infrared (NIR) moisture measurement with a four-wavelength sensor were evaluated (choice of binder used in granulation liquid and the increase in particle size). An entire NIR spectrum is not necessary for the measurement of water, and often the use of only a few NIR wavelengths around the water band enables reliable and high-speed detection of moisture. Glass ballotini and microcrystalline cellulose (MCC) were used as model test materials. The binders studied were poly[1-(2-oxo-1-pyrrolidinyl)ethylene] (PVP) and gelatin. Full off-line NIR spectra of test materials at different levels of binder solutions were measured. The major spectral features for both the binders were bands around 1700 nm (first overtones CH related stretches) and 2200 nm (combination bands). Gelatin also had an NH band around 1500 nm (first overtones of NH stretches) and combination bands at about 2050 nm. Particle size effects were observed as an increase in spectra baseline. All these factors should be considered when choosing NIR wavelengths used for detection of water with a fixed wavelength set-up. A robust calibration model enables the development of in-process control of wet granulation processes.

Hydrate Formation During Wet Granulation Studied by Spectroscopic Methods and Multivariate Analysis

AbstractPurpose. 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.

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.

Intestinal mucosa permeability following oral insulin delivery using core shell corona nanolipoparticles

Chitosan nanoparticles (NC) have excellent capacity for protein entrapment, favorable epithelial permeability, and are regarded as promising nanocarriers for oral protein delivery. Herein, we designed and evaluated a class of core shell corona nanolipoparticles (CSC) to further improve the absorption through enhanced intestinal mucus penetration. CSC contains chitosan nanoparticles as a core component and pluronic F127-lipid vesicles as a shell with hydrophilic chain and polyethylene oxide PEO as a corona. These particles were developed by hydration of a dry pluronic F127-lipid film with NC suspensions followed by extrusion. Insulin nested inside CSC was well protected from enzymatic degradation. Compared with NC, CSC exhibited significantly higher efficiency of mucosal penetration and, consequently, higher cellular internalization of insulin in mucus secreting E12 cells. The cellular level of insulin after CSC treatment was 36-fold higher compared to treatment with free insulin, and 10-fold higher compared to NC. CSC significantly facilitated the permeation of insulin across the ileum epithelia, as demonstrated in an ex vivo study and an in vivo absorption study. CSC pharmacological studies in diabetic rats showed that the hypoglycemic effects of orally administrated CSC were 2.5-fold higher compared to NC. In conclusion, CSC is a promising oral protein delivery system to enhance the stability, intestinal mucosal permeability, and oral absorption of insulin.

Raman spectroscopy in pharmaceutical product design

Almost 100 years after the discovery of the Raman scattering phenomenon, related analytical techniques have emerged as important tools in biomedical sciences. Raman spectroscopy and microscopy are frontier, non-invasive analytical techniques amenable for diverse biomedical areas, ranging from molecular-based drug discovery, design of innovative drug delivery systems and quality control of finished products. This review presents concise accounts of various conventional and emerging Raman instrumentations including associated hyphenated tools of pharmaceutical interest. Moreover, relevant application cases of Raman spectroscopy in early and late phase pharmaceutical development, process analysis and micro-structural analysis of drug delivery systems are introduced. Finally, potential areas of future advancement and application of Raman spectroscopic techniques are discussed.