Modification of the Physicochemical Properties of Active Pharmaceutical Ingredients via Lyophilization (original) (raw)
Related papers
2013
Freeze-drying is a method of removing water by sublimation of ice crystals from frozen material. Suitable parameters of process application allow us to obtain best quality products compared to products dried with traditional methods. In pharmaceutical field lyophilization has become important subject to ongoing development and its expansion. Lyophilization is common, but cost intensive and hence one of the key objectives during freeze-drying process development is to minimize the drying time (mainly primary drying time, which is the longest of the three steps in freeze-drying). However, increasing the shelf temperature into secondary drying before all of the ice is removed from the product will likely cause collapse or eutectic melt. Thus, from product quality as well as process economics standpoint, it is very critical to detect the end of primary drying. This review focused on the recent advances and its targets in near future. At first, the principle, steps involved, formulation ...
Future Journal of Pharmaceutical Sciences
Background Process intensification is a major hurdle in pharmaceutical process scale-up. Solvent removal strategies have limited the effectiveness of the overall stability of pharmaceutical formulations. The main aim of present review article is to focus on the use of the freeze-drying process in pharmaceuticals, biopharmaceuticals and nanoderived therapeutics and their translation into commercial viable products. Unwavering efforts of scientists in the process intensification of lyophilization promote unique features of products for commercialization. Regulatory agencies are promoting the utilization of a quality-by-design approach to improve product characteristics. Among 300 FDA-approved pharmaceutical industries, 50% of products are freeze-dried. The freeze-drying process is costlier and requires more time than other drying methodologies. Unstable pharmaceutical dispersions and solutions can be preferably stabilized by using the freeze-drying method. Main text This review highli...
A Review on Freeze Drying Process of Pharmaceuticals
Freeze-drying is a method of removing water by sublimation of ice crystals from frozen material. Suitable parameters of process application allow us to obtain best quality products compared to products dried with traditional methods. In pharmaceutical field lyophilization has become important subject to ongoing development and its expansion. Lyophilization is common, but cost intensive and hence one of the key objectives during freeze-drying process development is to minimize the drying time ( mainly primary drying time, which is the longest of the three steps in freeze-drying). However, increasing the shelf temperature into secondary drying before all of the ice is removed from the product will likely cause collapse or eutectic melt. Thus, from product quality as well as process economics standpoint, it is very critical to detect the end of primary drying. This review focused on the recent advances and its targets in near future. At first, the principle, steps involved, formulation aspects and importance of lyophilization, methods of lyophilization with detection of end point in lyophilization was explained.
Journal of Pharmaceutical Sciences, 2001
In a companion paper we show that the freezing of samples in vials by shelf-ramp freezing results in significant primary drying rate heterogeneity because of a dependence of the ice crystal size on the nucleation temperature during freezing.1 The purpose of this study was to test the hypothesis that post-freezing annealing, in which the product is held at a predetermined temperature for a specified duration, can reduce freezing-induced heterogeneity in sublimation rates. In addition, we test the impact of annealing on primary drying rates. Finally, we use the kinetics of relaxations during annealing to provide a simple measurement of Tg′, the glass transition temperature of the maximally freeze-concentrated amorphous phase, under conditions and time scales most appropriate for industrial lyophilization cycles. Aqueous solutions of hydroxyethyl starch (HES), sucrose, and HES:sucrose were either frozen by placement on a shelf while the temperature was reduced (“shelf-ramp frozen”) or by immersion into liquid nitrogen. Samples were then annealed for various durations over a range of temperatures and partially lyophilized to determine the primary drying rate. The morphology of fully dried liquid nitrogen-frozen samples was examined using scanning electron microscopy. Annealing reduced primary drying rate heterogeneity for shelf-ramp frozen samples, and resulted in up to 3.5-fold increases in the primary drying rate. These effects were due to increased ice crystal sizes, simplified amorphous structures, and larger and more numerous holes on the cake surface of annealed samples. Annealed HES samples dissolved slightly faster than their unannealed counterparts. Annealing below Tg′ did not result in increased drying rates. We present a simple new annealing–lyophilization method of Tg′ determination that exploits this phenomenon. It can be carried out with a balance and a freeze-dryer, and has the additional advantage that a large number of candidate formulations can be evaluated simultaneously. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:872–887, 2001
Scientific Reports
Conversion into the amorphous form enhances the dissolution of poorly soluble drugs, however the barrier to market for medicines containing an amorphous drug is poor stability. The aim was to produce the amorphous form of a drug within a capsule, without thermal or mechanical stress during manufacture. To facilitate this aim, the mechanism for drug-polymer interaction was explored. Nifedipine and polyvinylpyrrolidone were dissolved in tert-butanol at different drug/polymer ratios. These solutions were dispensed into gelatin capsules and freeze-dried. Differential scanning calorimetry (DSC) & novel FT-IR analysis based on peak symmetry measurements confirmed the absence of crystallinity when polyvinylpyrrolidone exceeded 50%w/w. Capsules containing 10 mg of nifedipine were amorphous and stable for over 3 months at ≈40 °C. Evidence of hydrogen bonding between the N-H group of nifedipine and the C=O group of PVP was observed and this interaction inhibited nifedipine crystallisation. PVP's high affinity for water and the nifedipine-polymer interaction lead to a significant dissolution rate enhancement. The freeze-dried capsule, 10%w/w nifedipine/PVP, had the highest dissolution rate constant of 0.37 ± 0.05 min −1 , and the lowest time to achieve 50% dissolution or t 1/2 of 1.88 ± 0.05 min. This formulation reached 80% dissolved in less than 6 min whereas the equivalent marketed liquid filled nifedipine capsule took 3 times longer to reach 80% dissolution. The biopharmaceutical classification system (BCS) ranks drugs in accordance to their solubility and permeability 1 , the dominating factors that influence the oral bioavailability of drugs 2, 3. Class II BCS, drugs with high permeability but low solubility, form a large number of the lead compounds generated by pharmaceutical research, but their low oral bioavailability reduces class II's developability into medicines 4. Due to limited aqueous solubility, the absorption of class II BCS drugs is hindered 1. This may be improved through formulation strategies, for example rendering the drug into its amorphous form 3, 5. An effective approach for enhancing the kinetic solubility and dissolution rate is to molecularly disperse a drug in a solubilizing carrier, thus inhibiting crystallisation and maintaining the drug within a disordered or amorphous structure 6. Despite the benefits of this strategy, amorphous drugs are not widely used in the pharmaceutical industry 6, 7 as most methods of generating amorphous materials expose the drug to thermal or mechanical stress, which leads to chemical degradation and re-crystallisation of the amorphous solid. For example, solid polymer-drug solutions maybe prepared using hot-melt extrusion (HME), a process limited to thermally stable drugs 4, 8. Thus, less aggressive methods for rendering poorly water soluble drugs (PWSD's) into amorphous medicines are required 6. Solvent evaporation methods 9 , where a drug and polymer are dissolved in a common volatile solvent, which is then removed via spray or freeze-drying ensures moderate to low heat exposure 10-17. Water is the principle solvent used for freeze-drying 18 which puts PWSD's at a disadvantage, as acceptable concentrations of the PWSD in the aqueous feed solutions are impossible to achieve. Some organic solvents may
LYOPHILIZATION -PROCESS AND OPTIMIZATION FOR PHARMACEUTICALS
In this 21 st century, Lyophilization emerges to be a novel trend for the drying of pharmaceuticals and biological that are thermolabile or are unstable in aqueous form but stable for longer periods in their dried form. This article provides an overview on the process of lyophilization, how the freeze drying cycle is designed, discussing several important parameters which are important for understanding of this process as well as their role in the designing of an optimized freeze drying cycle, so that a robust and economical process of lyophilization can be developed which does not impact the product quality. It also describes the use of this process in various industries.
PDA journal of pharmaceutical science and technology / PDA
Saccharides, including sucrose, trehalose, mannitol, and sorbitol, are commonly employed as stabilizers, cryoprotectants, and/or tonicity adjusters in protein formulations. During the thawing of a protein-containing formulated bulk drug substance conducted prior to a drug product (DP) filling operation, a white, crystalline precipitate was observed. In addition, upon thawing, vial breakage was observed for filled DP that had been previously frozen at -40 °C. To investigate the causes of both phenomena, the freeze/thaw behavior of the formulation components was studied. Multiple physical characterization techniques, including differential scanning calorimetry (DSC), electrical resistance measurements, thermomechanical analysis (TMA), and powder X-ray diffraction (PXRD), were utilized to characterize the formulations. The PXRD pattern of precipitate collected from thawed bulk was consistent with that of a mannitol control. An exothermic transition observed by DSC, a sharp increase in ...
Spray Freeze-drying – The Process of Choice for Low Water Soluble Drugs?
2002
Most of the novel highly potent drugs, developed on the basis of modern molecular medicine, taking into account cell surface recognition techniques, show poor water solubility. A chemical modification of the drug substance enhancing the solubility often decreases the pharmacological activity. Thus, as an alternative an increase of the solubility can be obtained by the reduction of the size of the drug particles. Unfortunately, it is often difficult to obtain micro or nanosized drug particles by classical or more advanced crystallization using supercritical gases or by milling techniques. In addition, nanosized particles are often not physically stable and need to be stabilized in an appropriate matrix. Thus, it may be of interest to manufacture directly nanosized drug particles stabilized in an inert hydrophilic matrix, i.e. nanostructured and nanocomposite systems. Solid solutions and solid dispersions represent nanostructured and nanocomposite systems. In this context, the use of the vacuum-fluidized-bed technique for the spray-drying of a low water soluble drug cosolubilized with a hydrophilic excipient in a polar organic solvent is discussed. In order to avoid the use of organic solvents, a special spray-freeze-drying technique working at atmospheric pressure is presented. This process is very suitable for temperature and otherwise sensitive drugs such as pharmaproteins.
International journal of pharmaceutics, 1999
Many pharmaceuticals, either by accident or design, may exist in a total or partially amorphous state. Consequently, it is essential to have an understanding of the physico-chemical principles underpinning the behaviour of such systems. In this discussion, the nature of the glassy state will be described, with particular emphasis on the molecular processes associated with glass transitional behaviour and the use of thermal methods for characterising the glass transition temperature, Tg. The practicalities of such measurements, the significance of the accompanying relaxation endotherm and plasticization effects are considered. The advantages and difficulties associated with the use of amorphous drugs will be outlined, with discussion given regarding the problems associated with physical and chemical stability. Finally, the principles of freeze drying will be described, including discussion of the relevance of glass transitional behaviour to product stability.