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Advanced Drug Delivery Reviews (v.64, #5)
Calorimetry and complementary techniques to characterize frozen and freeze-dried systems by Prakash Sundaramurthi; Raj Suryanarayanan (pp. 384-395).
Lyophilization is a commonly used drying technique for thermolabile pharmaceuticals. Crystallization of formulation components may occur during various stages of the freeze-drying process. In frozen solutions, while crystallization of bulking agents is desirable, both from processing and product-elegance perspectives, buffer salt crystallization can cause a significant pH shift. Lyoprotectants (compounds that protect macromolecules, both during freeze-drying and subsequent storage) are effective only when retained amorphous. This review presents numerous applications of differential scanning calorimetry to characterize pharmaceutical systems in frozen state. These studies are aimed at defining the processing parameters and optimizing the freeze-drying cycle. Low temperature pH measurement and sub-ambient X-ray diffractometry served as excellent complementary tools in the characterization of frozen systems. The phase behavior of the systems during annealing (of frozen solutions), primary and secondary drying were monitored by X-ray diffractometry. Finally, the interplay of formulation composition and processing parameters on the development and optimization of freeze-drying cycles are reviewed.Display Omitted
Keywords: Differential scanning calorimetry; X-ray diffractometry; Low temperature pH measurement; Frozen solution characterization; Phase transformation; Freeze-drying; Buffer crystallization; Lyoprotectant crystallization
Evaluation of amorphous solid dispersion properties using thermal analysis techniques by Jared A. Baird; Lynne S. Taylor (pp. 396-421).
Amorphous solid dispersions are an increasingly important formulation approach to improve the dissolution rate and apparent solubility of poorly water soluble compounds. Due to their complex physicochemical properties, there is a need for multi-faceted analytical methods to enable comprehensive characterization, and thermal techniques are widely employed for this purpose. Key parameters of interest that can influence product performance include the glass transition temperature (Tg), molecular mobility of the drug, miscibility between the drug and excipients, and the rate and extent of drug crystallization. It is important to evaluate the type of information pertaining to the aforementioned properties that can be extracted from thermal analytical measurements, in addition to considering any inherent assumptions or limitations of the various analytical approaches. Although differential scanning calorimetry (DSC) is the most widely used thermal analytical technique applied to the characterization of amorphous solid dispersions, there are many established and emerging techniques which have been shown to provide useful information. Comprehensive characterization of fundamental material descriptors will ultimately lead to the formulation of more robust solid dispersion products.Display Omitted
Keywords: Calorimetry; Mobility; Glass transition; Miscibility; Crystallization
Fast-Scan DSC and its role in pharmaceutical physical form characterisation and selection by James L. Ford; Timothy E. Mann (pp. 422-430).
Conventional rate Differential Scanning Calorimetry (DSC) has been used for many years as a tool in the analysis of pharmaceutical materials. In recent years an extension of the technique to include fast heating and cooling rates has become more prevalent. Broadly termed Fast-Scan DSC, this review examines the current applications of this technique to the characterisation and selection of pharmaceutical materials. Its increasing use encompasses the characterisation of amorphousness in crystalline materials, the characterisation of polymorphs and polymorphic transitions, the solubility of drugs in polymers, and characterisation of dosage forms. Notwithstanding the advantages of analytical speed in analytical turnover, the review emphasises the advantages of Fast-Scan DSC in its sensitivity which allows the separation of overlapping thermal events, the reduction it provides in degradation during the scanning process and its role in determining solubility in waxy and polymeric based systems.A comparison of the uses of Fast-Scan DSC to modulated DSC techniques and localised thermal analysis is also given.Display Omitted
Keywords: Differential Scanning Calorimetry; Fast-Scan DSC; High speed DSC; HyperDSC™; Glass transition; Amorphicity; Polymorphism; Polymorphic purity; Drug-solubility
Isothermal microcalorimetry for quantifying amorphous content in processed pharmaceuticals by Simon Gaisford (pp. 431-439).
Many processing steps can result in generation of partially amorphous materials. While the fraction of disorder may be low (typically up to 5% w/w) its location primarily on particle surfaces means its effects might be significant, especially in regard to powder flow and force of adhesion. Quantification of small amorphous contents is thus becoming an important part of product development. Isothermal microcalorimetry can be used as an assay for amorphous content by controlling the relative humidity or relative vapour pressure in the sample ampoule. The technique is very sensitive (typically detecting less than 1% w/w amorphous content) and universally applicable to pharmaceutical powders. However method design and data interpretation are critical factors in successful assay design. This article discusses methods and techniques and reviews current pharmaceutical applications to aid assay design.Display Omitted
Keywords: Isothermal microcalorimetry; Amorphous content quantification assay; Gas perfusion; Pharmaceutical
Pharmaceutical applications of dynamic mechanical thermal analysis by David S. Jones; Yiwei Tian; Osama Abu-Diak; Gavin P. Andrews (pp. 440-448).
The successful development of polymeric drug delivery and biomedical devices requires a comprehensive understanding of the viscoleastic properties of polymers as these have been shown to directly affect clinical efficacy. Dynamic mechanical thermal analysis (DMTA) is an accessible and versatile analytical technique in which an oscillating stress or strain is applied to a sample as a function of oscillatory frequency and temperature. Through cyclic application of a non-destructive stress or strain, a comprehensive understanding of the viscoelastic properties of polymers may be obtained. In this review, we provide a concise overview of the theory of DMTA and the basic instrumental/operating principles. Moreover, the application of DMTA for the characterization of solid pharmaceutical and biomedical systems has been discussed in detail. In particular we have described the potential of DMTA to measure and understand relaxation transitions and miscibility in binary and higher-order systems and describe the more recent applications of the technique for this purpose.Display Omitted
Keywords: Dynamical mechanical thermal analysis; Polymeric materials; Viscoelasticity; Biomedical polymers; Glass transition
Thermal scanning probe microscopy in the development of pharmaceuticals by Xuan Dai; Jonathan G. Moffat; John Wood; Mike Reading (pp. 449-460).
The ability to characterize the physical and chemical properties of dosage forms is crucial to a more complete understanding of how vehicles for drug delivery behave and therefore how effective they are. Spatially resolved characterization that enables the visualization of properties on the nanoscale is particularly powerful. The usefulness of scanning probe microscopy (SPM) in the field of drug delivery is becoming increasingly well established and the use of thermal probes offers new capabilities thus enabling SPM to provide more and sometimes unique information. One type of measurement enabled by thermal probes is determining transition temperatures by means of local thermal analysis. The ability to identify and characterize materials in this way has found applications in characterizing a wide range of dosage forms. A complimentary thermal probe technique is photothermal infrared microspectroscopy (PTMS). PTMS offers a variety of advantages over more conventional approaches including the ability analyze compacts without the need for thin sections. It is also able to achieve sub-micron spatial resolution. Thermal probe techniques can characterize pharmaceutical dosage forms in terms of their physical properties and their chemical composition.Display Omitted
Keywords: AFM; SPM; Microthermal; Nanothermal; Photothermal infra-red spectroscopy; PTMS; PTIR; infra-red imaging
Advances in simultaneous DSC–FTIR microspectroscopy for rapid solid-state chemical stability studies: Some dipeptide drugs as examples by Shan-Yang Lin; Shun-Li Wang (pp. 461-478).
The solid-state chemistry of drugs has seen growing importance in the pharmaceutical industry for the development of useful API (active pharmaceutical ingredients) of drugs and stable dosage forms. The stability of drugs in various solid dosage forms is an important issue because solid dosage forms are the most common pharmaceutical formulation in clinical use. In solid-state stability studies of drugs, an ideal accelerated method must not only be selected by different complicated methods, but must also detect the formation of degraded product. In this review article, an analytical technique combining differential scanning calorimetry and Fourier-transform infrared (DSC–FTIR) microspectroscopy simulates the accelerated stability test, and simultaneously detects the decomposed products in real time. The pharmaceutical dipeptides aspartame hemihydrate, lisinopril dihydrate, and enalapril maleate either with or without Eudragit E were used as testing examples. This one-step simultaneous DSC–FTIR technique for real-time detection of diketopiperazine (DKP) directly evidenced the dehydration process and DKP formation as an impurity common in pharmaceutical dipeptides. DKP formation in various dipeptides determined by different analytical methods had been collected and compiled. Although many analytical methods have been applied, the combined DSC–FTIR technique is an easy and fast analytical method which not only can simulate the accelerated drug stability testing but also at the same time enable to explore phase transformation as well as degradation due to thermal-related reactions.This technique offers quick and proper interpretations.Display Omitted
Keywords: Abbreviations; ACE; angiotensin converting enzyme; API; active pharmaceutical ingredient; APM; aspartame; DEA; dielectric thermal analysis; DIL; dilatometry; DKP; diketopiperazine; DMTA; dynamic mechanical thermal analysis; DSC; differential scanning calorimetry; DTA; differential thermal analysis; EGA; evolved gas analysis; ENAL; enalapril; FTIR; Fourier transform infrared; GC; gas chromatography; HPLC; high-performance liquid chromatography; HSM; Hot-stage microscopy; ICH; international conference of harmonization; IR; infrared; LC–MS; liquid chromatography–mass spectrometry; LIS; lisinopril; MS; mass spectroscopy; NIR; near infrared; NMR; nuclear magnetic resonance; R&D; research and development; SEM; scanning electron microscope; SMCR; self-modeling curve resolution; STA; simultaneous thermal analysis; SVD; singular value decomposition; TA; thermal analysis; TGA; thermogravimetric analysis; TMA; thermomechanical analysis; TOA; thermo-optical analysis; XRD; X-ray diffractometerSolid-state chemistry; Dipeptides; Stability; DSC–FTIR; DSC; Dehydration; Intramolecular cyclization; Diketopiperazines