Brian D. Hoit, MD

• Director of Echocardiography
• University Hospitals Health System
• Professor of Medicine, Physiology and Biophysics
• Case Western Reserve University
• Cleveland, Ohio

This approach cooking cholesterol lowering foods buy crestor 10mg with amex, which has the advantage of not requiring a solution manufacturing step in production cholesterol whey protein purchase crestor with american express, is likely to result in incomplete hydration of the polymers during processing cholesterol in yard eggs buy crestor 5mg with amex, which will affect the quality of the final granulate cholesterol test fasting guidelines order crestor on line amex. The level of binder used needs to be a balance between the level required to produce a robust cholesterol zly i dobry normy buy discount crestor 20mg, compressible granulate and the biopharmaceutical properties cholesterol levels chart south africa cheap crestor american express. As the granule strength increases, there is often an adverse effect on disintegration and dissolution. To optimize the dissolution of a drug from a granulated product, it is important that the granule should disintegrate into its primary particles as rapidly as possible, and it is usual to position at least a portion of any disintegrant inside the granules. A number of processing methods are commonly used within the pharmaceutical industry. Each method will impart particular characteristics and, as such, granulates produced by each method may not be equivalent in terms of either their physical properties (which will influence subsequent performance on tablet machines) or their biopharmaceutical properties. This latter point is well recognized by regulatory authorities that regard changes in the granulation method as potentially having a significant effect on the bioavailability of poorly soluble, poorly permeable compounds. This document concludes that changing the type of granulation process used can, for some drug substances, result in the need to perform a bioequivalence study prior to the change being granted regulatory approval. The three main methods of producing pharmaceutical granulates are low-shear granulation, high-shear granulation, and fluid bed granulation. Low-shear mixers encompass machines such as Z-blade mixers and planetary mixers, which, as their names suggest, impart relatively low shear stresses onto the granulate. Widely used in the past, this approach has largely been superseded by high-shear mixers. The low level of shear applied is often insufficient to ensure good powder mixing, so a premix is often required. The process is forgiving in terms of the amount of liquid added, although it does result in long granulation times. The degree of ball growth tends to be uncontrolled because there is insufficient shear to break up the plastic agglomerates, so a wet screening stage is almost always necessary prior to drying to reduce the larger agglomerates. High-shear granulators are closed vessels that normally have two agitators; an impeller, which normally covers the diameter of the mixing vessel, and a small chopper positioned perpendicular to the impeller. The powders are dry mixed using the impeller, and then the granulating fluid is added. Wet massing takes place using the impeller and the chopper, and granulation is usually completed in a number of minutes. The granulation process can be controlled using an appropriate combination of impeller and chopper speeds and time. The ability of the chopper to limit the size of the agglomerates can negate the need for a wet screening stage for many granulates. High-shear mixers provide a greater degree of densification than the low-shear mixers. This, combined with the relatively short processing times, can lead to the process being very sensitive to the amount of granulating liquid added. In both high-shear and low-shear mixers, the mode of liquid addition can affect the quality of the final product. Slow spraying leads to the most uniform distribution of liquid but can increase the overall processing time. Pouring the liquid onto the powder will result initially in large overwet granulates being formed. The mixer needs to impart sufficient energy to the system to break up the agglomerates to achieve uniform distribution of liquid. Fluid bed granulation involves spraying the dry powder with a granulating fluid inside a fluid bed drier. The powder is fluidized in heated air and then sprayed with the granulating fluid. When all the granulating liquid has been added, the fluidization of the powder continues until the granules are dry. Advantages of this technique are that the granulation and drying are performed in a continuous manner in the same vessel, and there is no need for a wet screening operation. Nucleation occurs by random collisions between the droplets of granulating fluid and particles until all the individual particles have been incorporated into agglomerates. Oral Solid Dosage Forms 407 the main difference in the granules produced by different methods was their final density, high-shear mixers producing denser granules than low-shear granulators, which in turn produced denser granules than fluid bed granulations. Disintegration times were greater for tablets produced from the denser granulates. Extrusion/Spheronization One specialized method of particle agglomeration is extrusion and spheronization, to produce spherical or near-spherical particles. Such particles are suitable for coating with release, modifying coats to produce controlled-release formulations. The particles are usually filled into hard gelatin capsules for administration to patients. This step is performed using equipment similar to that of conventional wet granulation, though the quantity of water added is greater, resulting in a plastic mass rather than granules. The mass is then extruded, that is, forced through a screen containing circular holes, to form a spaghetti-like extrudate. The extrudate is cut into lengths roughly twice the diameter of the holes and rolled by frictional and centrifugal forces on a rotating grooved plate known as a marumerizer or spheronizer. The rolling action compresses the cylinder along the length and rounds the ends, forming dumbbells, which become further compressed along their length to form spheres. The spheroids are discharged from the spheronizer and dried, usually by fluid bed drying. Microcrystalline cellulose appears to be unique in its ability to form spheroids by this method due perhaps to its ability to hold onto the water during extrusion. The squeezing of the wet mass through a screen during extrusion forces most materials to lose water, and the resulting extrudates do not have the necessary plasticity to form spheroids. The robustness of microcrystalline cellulose means that for most low-dose drugs, it is possible to make spheroids, certainly if the drug loading is below 10%. Two factors appear to be required for success, the mass must retain the water during the extrusion process, and the extrudate must have the appropriate rheological properties. The different shear forces will have an effect on the water distribution in the extrudates. As the water level is critical for optimizing the spheronization process, it is clear that the formulation development and process development need to be considered as one for this type of process. Dry Granulation It is possible to form granulates without the addition of a granulating fluid, by techniques generically referred to as dry granulation. These methods are useful for materials that are sensitive to heat and moisture, but which may not be suitable for direct compression. Dry granulation involves the aggregation of particles by high pressure to form bonds between particles by virtue of their close proximity. Two approaches to dry granulation are used in the pharmaceutical industry: slugging and roller compaction. In either method, the material can be compacted with a binder to improve the bonding strength. Granulation by slugging is, in effect, the manufacture of large compacts by direct compression. The slugs produced are larger than tablets and are often poorly formed tablets exhibiting cracking and lamination. As with tablets, it may be necessary to add a lubricant to prevent the compacts sticking to the punches and dies. The compressed material is broken up and sieved to form granules of the appropriate size. The granules are then blended with disintegrant and lubricant, and compressed on a normal tablet machine. The rollers may be flat, which will produce sheets of compacted material, or they may be dimpled, in which case, briquettes in the shape of the dimples will be formed. Selection of the Appropriate Process the methods of formulating and manufacturing tablets have been described in the preceding sections. Each method has certain unique benefits and advantages as well as drawbacks, and these are summarized in Table 14. For any given compound, there will normally be more than one approach that is technically feasible, so how does one choose which approach to take For most formulators, the choice is strongly influenced by the philosophy of the production department of the company in which they work. Different companies can have very different philosophies; some believe that the cost savings of direct compression are such that attempts should be made to formulate all tablets by this route, other companies feel that wet granulation is a more robust process, and should be used even when a compound looks amenable to the direct compression route. Tablet Coating For some tablets, compression marks the final stage of the production process, but many formulations involve coating the compressed tablet. Sugar coating was the most commonly used method until the 1970s, when it was largely superseded by film coating. Sugar Coating Sugar coating, as its name suggests, involves coating tablets with sucrose. The process involves applying a number of aqueous solutions of sucrose, together with additional components, which gradually build Table 14 Manufacturing and Formulating Tablets-Advantages and Disadvantages Method Direct compression Advantages Simple, cheap process. Disadvantages Not suitable for all drugs, generally limited to low-dose compounds. Stability issues for moisture-sensitive and thermolabile drugs with aqueous granulation. Wet granulation (aqueous) Wet granulation (nonaqueous) Dry granulation (slugging) Dry granulation (roller compaction) 410 Davies up into a smooth, aesthetically pleasing coat. The final coat can account for up to 50% of the final tablet weight, and will result in a significant increase in the tablet size. Traditionally, sugar coating has been performed in coating pans in which the tablets are tumbled. With the appropriate tablet load and rotation speed, the tablets are tumbled in a three-dimensional direction. The pan is supplied with a source of warm air for drying and an extraction system to remove moist air and dust. The coating solution is ladled onto the tablet bed and is distributed around the tablets by their tumbling action. The tablets are then tumbled for a period of time to allow the coating to dry before a further quantity of solution is added. A dusting powder may be sprinkled onto the surface of the tablets during the drying phase to prevent the tablets sticking together. If too little is added, then not all tablets will pick up some of the coating, and an uneven distribution will result. The cycle of wetting and drying is continued until the desired amount of coating has been applied to the tablets. One of the reasons for coating tablets is to protect the drug substance from environmental factors such as moisture, so it is important that the coating solution does not penetrate into the core. Traditionally, a coating of shellac dissolved in ethanol was applied, but this has largely been replaced by the use of synthetic water-resistant polymers such as cellulose acetate phthalate or polyvinylacetate phthalate. The challenge for the formulator is to optimize the quantity of subcoat applied to ensure the core is protected while minimizing the effect on drug release. Oral Solid Dosage Forms 411 the subcoat is an adhesive coat on which the smoothing coat can be built. A second purpose of the subcoat is to round off the sharp corners of the tablet to produce a smooth surface. The subcoat is a mixture of a sucrose solution and an adhesive gum, such as acacia or gelatin, which rapidly distributes over the tablet surface. A dusting follows each application of solution with a subcoat powder containing materials such as calcium carbonate, calcium sulfate, acacia, talc, and kaolin that help to produce a hard coat. The application of the subcoat continues until the tablets have a rounded appearance and the edges are well covered. The smoothing coat consists of the majority of the tablet bulk, and provides the tablet with a smooth finish. The coat consists of sucrose syrup, which may contain starch or calcium carbonate. Each application is dried, and layers are added until the required bulk has been achieved. The last few coatings will consist of sucrose solution and colorants, where required. The colorants may be either soluble dyes or lakes, lakes often being preferred because a uniform color is easier to achieve with them. Film Coating Film coating involves the application of a polymer film to the surface of the tablet and, in contrast to sugar coating, only adds up to 5% weight to the final tablet, with a negligible increase in tablet size. It is a technique, which, while used mainly to coat tablets, can also be applied to hard gelatin capsules, soft gelatin capsules, and multiparticulate systems such as spheroids. The method of application of the coat differs from sugar coating in that the coating suspension is sprayed directly onto the surface of the tablets, and drying occurs as soon as the coat hits the tablet surface. To achieve this, the tablet only receives a small quantity of coat at a time, and the coat is built up in an intermittent manner. While the coating can be applied using a number of methods, all share the following properties: a method of atomizing the coating suspension, the ability to heat large volumes of air (which heat the tablets and facilitate the rapid drying of the applied coat), and a method of moving the tablets that ensures all tablets are evenly sprayed. The main methods of coating are modified conventional coating pans, side-vented pans, and fluid bed coating. When the technique of film coating was first applied to tablets, the coatings were suspended in organic solvents, and conventional coating pans were used. Additional air handling was required to provide the volume of air necessary to dry the tablets and to extract the vapors from drying. The nature of the pans was such that the drying air was only present on the surface of the tablet bed; there was no mechanism for it to percolate through it.

Nanotechnology involves materials in nanoscale from 1 to 100 nm and has been extensively studied for improving the diagnosis and treatment of disease [17 are high cholesterol foods bad cheap crestor online visa,18] cholesterol mg per day purchase 10 mg crestor overnight delivery, forming a new research area referred to as nanomedicine cholesterol medication for triglycerides buy generic crestor online. In cancer cholesterol levels elevated buy discount crestor 5 mg on-line, the delivery of anticancer agents has been highly regarded and several nanodelivered drugs have been used clinically cholesterol ratio 1.9 good purchase crestor mastercard. In this chapter cholesterol medication for stroke buy crestor with a mastercard, we introduce the recent progress in the application of nanotechnology for the treatment of melanoma with emphasis on the delivery of anticancer agents for targeted therapy and immunotherapy. Nanodelivery can concentrate the anticancer agents at the tumor site and increase the penetration of the drugs into cancer cells. Nanoparticles can be made to approximately 100 nm, allowing them to pass through the leakiness of tumor vasculature but not normal vessels [22]. The vasculature of a tumor is poorly organized and thus has larger gaps between endothelial cells. Therefore, off-target side effects can be reduced and dosages used can be increased. The targeted delivery is realized by attachment of specific antibodies, peptides, nuclear acid-based ligands, or small molecules that bind to proteins specifically and are highly expressed on cancer cells. The use of folic acid has a similar effect as its receptor is also increased in melanoma. Therefore, off-target side effects are still a problem although they may be reduced. Nanoparticles can protect drugs from biochemical degradation in the human body, thereby increasing circulating time [29]. Nanoparticles provide a shield for carried drugs, enabling them to avoid contact with enzymes in the blood. For example, liposomes can contain hydrophilic drugs in their core aqueous phase, protecting the drugs by their bilayer of lipids. Nanodelivery can facilitate combination therapy as it can carry multiple drugs simultaneously. Combination therapy is highly regarded as it can combine different anticancer modes to increase treatment efficacy. Polymers can be formed as dendrimers such as poly(aminoamine), poly(propyleneimine) and poly-L-lysine dendrimers. Paclitaxel is a mitosis inhibitor through blocking microtube dynamics in cell division. It is a hydrophobic drug and is therefore difficult to dissolve in water; human albumin increases its solubility. In animal experiments, nanodelivery increased paclitaxel transportation to the tumor site and decreased side effects. Clinical trials of nab-paclitaxel in breast cancer increased response rate and overall survival time. Chemotherapeutic agents kill both malignant and normal cells that are dividing [44]. Therefore, they are very toxic, limiting the dosage that can be safely administered. The application of nanodelivery to these chemotherapeutic agents has increased treatment efficacy and reduced side effects, enabling more chemotherapeutic agents to be applied to melanoma treatment. The outcomes of the trials in breast cancer are encouraging due to greatly improved pharmacokinetics and pharmacodynamics [45]. Thus it was also used for clinical trials for other cancers including metastatic melanoma. These trials showed that nabpaclitaxel was more tolerated and more effective against melanoma than free paclitaxel [46,48]. However, side effects like neutropenia, thrombocytopenia, neurosensory problems, fatigue, nausea, and vomiting are still common [47]. The concentration of etoposide at the tumor site was fourfold higher than free etoposide. Viral infections can also cause the activation of multiple signaling pathways to promote cancer. Many viruses have oncogenes that express oncoproteins to alter host cellular signaling pathways [59,60]. Signaling pathways have been associated with the prognosis of melanoma and inhibition of these signaling pathways has been studied for the treatment of melanoma [56,62]. Both genetic defects and environmental factors such as obesity and viral infection can activate intracellular signaling pathways to cause cancer. Nanotechnology could be used to increase the effects of inhibition of these signaling pathways. In particular, it can be used to deliver several inhibitors simultaneously, which can increase the therapeutic effect compared to just a single inhibitor. This indicates that combination therapy with nanodelivered signaling molecule inhibitors and free chemotherapeutic agents has an additive effect. This encourages further effort into the application of nanotechnology in melanoma. A polymer micelle was used to pack rapamycin together with paclitaxel, showing significantly superior effects in reducing tumor size in a xenograft breast cancer model compared to rapamycin or paclitaxel alone [78]. In order for cancer cells to proliferate quickly, they need a sufficient supply of blood. Nanotechnology has also been used for improving the effect of bevacizumab but it has not yet been tested in melanoma [81,82]. The side effects are also a problem for this new technology, thus limiting its application in the clinic. Inhibition of antiapoptotic proteins has been used to cause melanoma cell apoptosis [96]. Nanotechnology has been studied to increase the therapeutic effect of Bcl-2 inhibition. It is possible that the combination delivery with Mcl-1 may further increase its effectiveness. Deficiency in the immune system is associated with increased cancer incidence and drug resistance. Immunotherapy has been developed for cancer treatment either through stimulation of the immune system or suppression of immune checkpoint proteins. The major issues in cancer immune therapy are the low rate of responses and side effects such as autoimmune diseases. Immunostimulation Immunotherapy is used to improve the immune responses in patients with melanoma by increasing the clearance of cancer cells by cytotoxic T-cells or macrophages. In melanoma, several cytokines have been shown to have initial effects but the effects are limited by side effects [101]. Clinical trials revealed long-lasting effectiveness but the response rate was not high enough even with combination therapy. Macrophages promote phagocytosis, antigen presentation, and cytokine production to facilitate cancer cell elimination. The average tumor volume was reduced by 93%, this was not observed in mice with clodronate-depleted macrophages, indicating the effect was macrophagedependent. Therefore, the immune system was minimally affected and autoimmune responses can be avoided. Combination therapy has thus been explored to further increase the treatment efficacy of nanodelivered drugs. References [1] Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Applications of nanotechnology for melanoma treatment, diagnosis, and theranostics. The application of nanotechnology in melanoma treatment may bring an effective approach as it can concentrate anticancer agents into the site of the tumor to increase efficacy and reduce side effects. Results obtained from in vitro cell culture tests and in vivo animal experiments are promising. In addition, nanotheranotics allow us to monitor the distribution of nanodelivered drugs and therapeutic effects in a real-time fashion. A new direction is the nanodelivery of combination therapy, which may greatly improve treatment efficacy. Although some studies have been carried out, extensive investigation is still needed to produce a practical approach for melanoma treatment. There are many types of combination treatments available for selection in melanoma therapy. At present it is difficult to judge which approach is most suitable in terms of efficacy and side effects. An engineered nanoplatform for bimodal anticancer phototherapy with dual-color fluorescence detection of sensitizers. Multimodal polymer nanoparticles with combined 19F magnetic resonance and optical detection for tunable, targeted, multimodal imaging in vivo. A novel lipidbased nanomicelle of docetaxel: evaluation of antitumor activity and biodistribution. Multifunctional biodegradable polymer nanoparticles with uniform sizes: generation and in vitro anti-melanoma activity. Phase I clinical trial of hepatic arterial infusion of cisplatin in combination with intravenous liposomal doxorubicin in patients with advanced cancer and dominant liver involvement. Albumin-bound paclitaxel: the benefit of this new formulation in the treatment of various cancers. Cationic poly-l-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo. Evaluation in melanoma-bearing mice of an etoposide derivative associated to a cholesterol-rich nanoemulsion. Turning a water and oil insoluble cisplatin derivative into a nanoparticle formulation for cancer therapy. Prevention of obesity-associated colon cancer by (-)-epigallocatechin-3 gallate and curcumin. Inducible expression of (V600E) Braf using tyrosinase-driven Cre recombinase results in embryonic lethality. Combinational delivery of lipid-enveloped polymeric nanoparticles carrying different peptides for anti-tumor immunotherapy. Melanoma genetics and therapeutic approaches in the 21st century: moving from the benchside to the bedside. Management of toxicities associated with high-dose interleukin-2 and biochemotherapy. Effective melanoma immunotherapy with interleukin-2 delivered by a novel polymeric nanoparticle. Use of a nanoporous biodegradable miniature device to regulate cytokine release for cancer treatment. Co-delivery of cisplatin and rapamycin for enhanced anticancer therapy through synergistic effects and microenvironment modulation. The incidence and mortality rates for malignant melanoma have been increasing steadily since the 1960s, with an estimated 76,100 new cases and 9710 deaths in the United States in 2014 [1]. Major advances in immunology and an in-depth understanding of immune responses in tumorigenesis led to a shift in the prevailing dogma, so that now melanoma is considered not only a genetic disease, but also an immunological disorder. Melanoma can avoid immune recognition and elimination by disrupting antigen presentation mechanism, eg, downregulation of major histocompatibility complex class I molecules and disabling of the antigen processing machinery. Limitations of Conventional Treatments for Melanoma Melanoma is highly curable if detected at a very early stage. Moreover, immune suppression and immune escape also participate in melanomagenesis. Breakthroughs in the treatment of metastatic melanoma are based on the progress in understanding the oncogenic mutations and immunobiological properties of this cancer. However, the results are unfortunately overshadowed by a short median length of response and a high relapse rate [13e15]. Although the responses are more durable, only a minority of patients achieve clear, objective responses in contrast with targeted therapy, in which a majority of patients obtain an objective response [16e18]. Nanotechnology-Based Targeted Drug Delivery: A New Promising Strategy for Melanoma Treatment One of the main reasons leading to the low efficacy and therapy resistance of the conventional drugs mentioned earlier is the lack of selective delivery of therapeutic agents to tumor tissues. Furthermore, high systemic exposure to these drugs inevitably results in serious dose-limiting toxicities. Therefore, targeted delivery is of utmost importance to overcome current limitations in melanoma therapy. First, poor water solubility limits the bioavailability and reduces the efficacy of traditional anticancer drugs. Polymer bioconjugates, micelles, and liposomes are among the most commonly used nanocarriers for the delivery of these chemotherapeutic agents to melanoma to surmount the obstacles of low delivery efficiency and toxic adverse effects to normal tissues. Liposomes for chemotherapeutic drug delivery have also shown enhanced antimelanoma efficacy and improved survival compared with free drugs, but with less side effects [25]. Both of them inhibited tumor growth and extended survival in melanomabearing mice more efficiently and without apparent toxicity compared to the nontargeted control group [30,31]. Targeting the Integrins on the Surface of Endothelial Cells Associated With Melanoma Neovasculature Integrins are heterodimeric transmembrane glycoprotein receptors essential for tumor cell adhesion, migration, and invasion. Integrin family members avb3, avb5, and a5b1 are usually highly expressed on endothelial cells associated with melanoma neovasculature. Moreover, compared to mono-targeting, dual-targeting seems to be an even more effective method for anticancer drug delivery. For example, C16Y, a synthetic peptide with 12 amino acids, can bind to integrins avb3 and a5b1 on both tumor vasculature associated endothelial cells and tumor cells in melanoma-bearing mice [44]. More efficient melanoma growth inhibition using C16Y-modified liposomes was observed than that found with nontargeted control [44]. Targeting Melanoma-Associated AntigenPresenting Cells and Melanoma-Draining Lymph Nodes the great success obtained from the clinical trials of melanoma vaccines such as gp100 and Allovectin-7 suggests a new strategy in melanoma treatment. When exposed to alternating magnetic fields or heating with shortwave radio-frequency fields, the heat produced from the applied electromagnetic energy can kill melanoma cells either directly or through the heat-triggered drug release from thermal-responsive polymers.

As a rough guide cholesterol levels chart ireland generic crestor 5mg free shipping, angles less than 308 are usually indicative of good flow cholesterol lowering foods in hindi order generic crestor pills, while powders with angles greater than 408 are likely to be problematic cholesterol levels us order crestor 20 mg amex. Avalanching Behavior If a powder is rotated in a vertical disc cholesterol test mayo clinic cheap crestor 20 mg free shipping, the cohesion between the particles and the adhesion of the powder to the surface of the disc will lead to the powder following the direction of rotation until it reaches an unstable situation where an avalanche will occur cholesterol test monitor order crestor 10mg. After the avalanche cholesterol test before eating generic crestor 20mg overnight delivery, the powder will again follow the disc prior to a further avalanche. Measurement of the time between avalanches and the variability in time is a measure of the flow properties of the powder. To determine the degree of mixing obtained in a pharmaceutical operation, it is necessary to sample the mixture and determine the variation within the mix statistically. In assessing the quality of a mixture, the method of sampling is more important than the statistical method used to describe it. Unless samples that accurately represent the system are taken, any statistical analysis is worthless. Furthermore, to provide meaningful information, the scale of scrutiny of the powder mix should be such that the weight of sample taken is similar to the weight that the powder mix contributes to the final dosage form. Oral Solid Dosage Forms 375 A large number of statistical analyses have been applied to the mixing of powders. These tend to be indices where the variance of the actual mix is compared to the theoretical random mix. The statistics are beyond the scope of this text and can be found in a number of standard texts on powder technology (Rhodes, 1990). Segregation If a powder consisting of two materials, both having identical physical properties, is mixed for sufficient time, random mixing will eventually be achieved. Unfortunately, most pharmaceutical powders consist of mixtures of materials with differing properties. This leads to segregation, where particles of similar properties tend to collect together in part of the powder. When segregating powders are mixed, as the mixing time is extended, the powders appear to unmix, and equilibrium is reached between the action of the mixer, introducing randomness and the resistance of the particles due to segregation. While a number of factors can cause segregation, differences in particle size are by far the most important in pharmaceutical powders. There are a number of mechanisms by which segregation of different-sized particles can occur, and consideration should be given to these when designing pharmaceutical processes. Trajectory segregation occurs when a powder is projected horizontally in a fluid or gas; larger particles are able to travel greater horizontal distances than small particles before settling out. This could cause segregation at the end of conveyor belts or vacuum transfer lines. The upward velocity of this air may be sufficient to equal or exceed the terminal velocity of some of the smaller particles, and these will remain suspended as a cloud after the large particles have settled out. If a powder bed is handled in a manner that allows individual particles to move, a rearrangement in the packing of the particles occurs. If the powder contains particles of different sizes, there will be more opportunities for the smaller particles to drop, so there will be a tendency for these to move to the bottom of the powder, leading to segregation. This process can occur whenever movement of particles takes place, including when vibrating, shaking, and pouring. Ordered Mixing As stated above, differences in particle size are the most common cause of segregation in pharmaceutical powders. One exception to this is when one component of a powder mix has a very small particle size (< 5 mm) and the other is relatively large. In such circumstances, the fine powder may coat the surface of the larger particles, and the adhesive forces will prevent segregation. This is known as ordered mixing, and using this technique, it is possible to produce greater homogeneity than by random mixing. Knowledge of the behavior of powders under pressure, and the way in which bonds are formed between particles, is essential for the rational design of formulations. Powder in a container subjected to a low compressive force will undergo particle rearrangement until it attains its tapped bulk density. Ultimately, a condition is reached where further densification is not possible without particle deformation. If, at this point, the powder bed is subjected to further compression, the particles will deform elastically to accommodate induced stresses, and the density of the bed will increase with increasing pressure at a characteristic rate. Brittle materials will undergo fragmentation, and the fine particles formed will percolate through the bed to give secondary packing. Either mechanism, therefore, consists of at least two submechanisms, and the processes could be repeated on the secondary particles produced by the fracture until the porosity is at a minimum and the internal crystalline structure supports the compressional stress. Both processes will aid bonding to form a single compact, as plastic flow increases contact areas between particles irreversibly and fragmentation produces clean surfaces that bond strongly. The successful production of compacts depends on achieving high contact areas between uncontaminated surfaces. To fully understand the compaction behavior of a material, it is clear that it is necessary to be able to quantify its elasticity, plasticity, and brittleness. Measurement of Compaction Properties To characterize the compaction properties of a material or formulation, it must be possible to measure the relationship between the force applied to a powder bed and the volume of the powder bed. The positioning and installation of the load and displacement transducers are critical to obtain meaningful information. The topic of instrumentation is comprehensively covered by Ridgway and Watt (1988). There are three approaches that have been used to generate compaction information, as discussed below. Conventional Testing Machines Testing machines are widely used in materials science and engineering laboratories for the measurement of physical properties of various materials. Many of the basic principles of compaction and the test methodologies currently employed in pharmaceutical formulation have been developed on testing machines by the metallurgy and ceramic industries. The Oral Solid Dosage Forms 377 drawback with testing machines is that the compression speeds that can be achieved are well below those encountered on tabletting machines, so while they are of value in fundamental studies, they are not necessarily useful for predicting the behavior of a material or formulation in the factory. Conventional Tablet Machines the first tablet machines to be instrumented were single punch eccentric presses. While these provide useful information, the compression profiles differ from those of rotary tablet machines used for commercial production. The profile of a single punch involves the powder bed being compressed between a moving upper punch and a stationary lower punch, while on a rotary machine, both punches move together simultaneously. Consequently, rotary machines have been instrumented, even though this is technically more challenging than single punch machines. The instrumented rotary press provides information that is directly relevant to production conditions, although it should be borne in mind that profiles do vary between machines, and any results obtained may be peculiar to that machine. A major advantage of instrumented machines is that they provide information not only on the compaction properties but also on flow and lubrication. The disadvantage of using instrumented rotary machines is the quantity of material required to perform tests, making them unsuitable for preformulation activities, when material is in short supply. Compaction Simulators Compaction simulators are a development of testing machines. They consist of single punch machines in which the upper and lower punches are driven individually by hydraulic rams. The movement of the hydraulic rams is controlled by computer and can be programmed either to simulate the movement of any tablet machine or to follow a simple profile similar to a testing machine. The big advantage of the compaction simulator is that it can be used to prepare a single compact using a profile that might be encountered on a production machine, so only small quantities of material are required. Quantitative Compaction Data There are two principal types of compaction studies used to characterize material: pressure/ volume relationships and pressure/strength relationships. While ultimately it is the strength of a tablet that is important, the pressure/volume relationships provide the information about the compaction properties of a material that allows an appropriate formulation to be developed. Heckel Plots A large number of equations have been proposed to describe the relationship between pressure and volume reduction during the compaction process. Many of these have an empirical basis and may relate to a particular material or range of pressures, while others attempt to define the complete process of densification. The equation that has been most widely used to describe the compaction of pharmaceutical powders is the Heckel equation (Heckel, 1961). This equation, originally used to describe the densification of ceramics, is essentially a curve-fitting equation that provides reasonable correlation with the observed facts over a wide range of pressures. The equation is based on the premise that compaction is a first-order process where the rate at which pores within a powder can be eliminated is proportional to the number of pores present. As the compaction process continues, the number of pores continue to drop, and consequently, the rate of volume reduction per unit increase in pressure drops. Pharmaceutical powders do not produce perfect straight lines, and the type of deviation provides information about the compaction behavior of the material. A straight-line portion is obtained over a certain pressure range with a negative deviation at low pressures and a positive deviation at high pressures. The gradient of the straight-line portion of the plot is related to the reciprocal of the yield pressure of the material, and as such is a measure of the plasticity of the material. While the absolute values obtained for the yield pressure will be dependent on the equipment and test conditions employed, the relative values obtained under given test conditions will provide information about the compaction properties of materials. Table 4 displays the values for yield pressure obtained for excipients, known to have differing compaction properties, tested using a compaction simulator. Type A (plastic) exhibits parallel but distinct graphs for different size fractions, type B (fragmenting) exhibits particulate fragmentation at low pressures, with graphs becoming coincident at higher pressures, and type C (extremely plastic) is characterized by a small initial curved section, a low value of mean yield pressure, and a rapid approach to zero porosity at low pressure. The effect of compression speed on the yield pressure of a material has been suggested as a method of determining the time-dependent nature of materials compression properties (Roberts and Rowe, 1985). Elasticity While Heckel plots are able to distinguish between plastic and fragmenting mechanisms, they do not readily distinguish between plastic and elastic deformation. The data presented in Table 4 would suggest that microcrystalline cellulose and starch 1500 have very similar properties, yet the elastic nature of starch and its derivative products is well documented in the literature. Elasticity can be determined either by monitoring the elastic energy during the decompression phase of a compact within the die or by comparing the dimensions of the ejected compact with the dimensions of the compact within the die at peak compaction pressure. If punch force is plotted against punch tip displacement or punch tip separation, a curve with a progressively increasing slope is obtained, reaching a maximum force at the point of minimum separation. As the punch begins to retract, the compact will expand because of elastic recovery and will remain in contact with the punch. If the material being compressed is truly elastic, the curve for the decompression phase will overlay the compression phase. For a truly plastic material, the force will fall to zero immediately as the punch begins to retract. Pharmaceutical materials tend to show a combination of elastic and plastic deformation. This measure differs from the elastic energy in that it includes the viscous contribution to elastic recovery as well as the purely elastic behavior during the unloading period of compression. Whichever method is used to calculate the elasticity, it should be borne in mind that the punches will also display a degree of elasticity, and this must be allowed for when calculating punch separations at pressure. Indentation Hardness An alternative method of determining the plasticity and elasticity of a material is indentation hardness testing. The principle of indentation hardness testing is that a hard indenter of specified geometry, either a sphere or square-based pyramid, is pressed onto the surface of the test material with a measured load and the size of the indentation produced measured. The hardness of a material is the load divided by the area of the indentation to give a measure of the contact pressure. There are two types of hardness tests: static tests that involve the formation of a permanent indentation on the surface of the test material and dynamic tests in which a pendulum is allowed to strike the test material from a known distance. Vickers and Brinell tests, two examples of static methods, are the most commonly used methods for determining the hardness of pharmaceutical materials. In the Brinell test, a steel ball of diameter D is pressed on to the surface of the material, and a load F is applied for 30 seconds and then removed. Traditionally, it has been necessary to perform indentation testing on compacts because of the size of the indenters. The surfaces of compacts are not homogeneous, and this Oral Solid Dosage Forms 381 introduced variability. Recently, nanoindentation testers have been developed, which are capable of performing indentation tests on single crystals. Such testers offer significant potential for characterizing the mechanical properties of materials at an early stage of development. Pressure/Strength Relationships the strength of tablets has traditionally been determined in terms of the force required to fracture a specimen across its diameter, the diametral compression test. The fracture load obtained is usually reported as a hardness value, an unfortunate use of a term that has a specific meaning in materials science, associated with indentation. The use of the fracture load does not allow for compacts of different shapes, diameters, or thicknesses to be directly compared. The solution for tensile stresses can only be used for tablets that fail in tension, characterized by failure along the loaded diameter. The stresses developed in the tested convex tablets undergoing the diametral compression test have been examined by Pitt et al. Initially, most materials demonstrate an increase in tensile strength proportional to the compaction pressure applied. As the compaction pressure is increased, the tablet approaches zero porosity, and large increases in pressure are required to achieve small volume reductions, and consequently, small increases in bonding. Some materials will attain maximum strength, and subsequent increases in pressure will produce weaker tablets. Other materials also display an initial increase in strength proportional to the applied pressure, but the strength reaches a maximum before falling off sharply.

The different experimental designs (configurations and variables) and evaluation methods are highlighted cholesterol guidelines 2015 discount crestor american express. Finally cholesterol test boots the chemist best 20 mg crestor, we discuss the current state of the art and recommendations for the future quixx test cholesterol generic 10mg crestor fast delivery. Gold nanoparticles in various researches were applied topically or systemically for treatment of dermal conditions cholesterol levels lowering foods buy crestor canada, transcutaneous delivery of therapeutics ldl cholesterol in quail eggs cheap crestor 5 mg, or treatment and diagnosis of skin cancer cholesterol vs fat crestor 20mg visa. Surgical excision remains the standard treatment modality for skin cancers [16,17]. However, developing new treatment strategies could offer great benefits regarding reduced morbidity and mortality [16]. Systemically applied nanosized objects may accumulate in cancer cells due to the enhanced permeability and retention effect [18]. The conjugate showed efficient in vitro cellular uptake by human squamous carcinoma cells A431. The usage of surface plasmon resonance allows for enhanced light absorption and scattering cross-sections [25]. In contrast, topical application of nanotherapeutics seems like an attractive easy route to reach these skinlocalized cancers. Liposomes smaller than 100 nm exhibit poor stability and tend to fuse to decrease surface tension [29]. This tremendously reduces skin penetration ability and effective drug delivery [30]. Another area of interest is the transdermal delivery of therapeutics, especially biomacromoleculesdfor instance, peptides and proteins for transcutaneous vaccination. Skin layers contain antigen presenting cells, such as Langerhans cells in the epidermis, that initiate an immune response against exogenous antigens invading the skin. Transcutaneous vaccination will be an attractive needle-free immunization strategy [31]. This penetration enhancement was also shown to be a temporal effect, which was demonstrated via use of a small fluorescent dye (rhodamine B). The results showed a robust, persistent immune response observed from the significantly increased level of antiovalbumineimmunoglobulin G (IgG) over the immunization course [10]. However, translation of laboratory data to topical clinical applications appears to be still remote, as a result of the firmness of the skin as a barrier that is difficult to be penetrated passively. Accordingly, a deeper understanding of the penetration behavior of nanoparticulates is necessary for a better design of nanotherapeutics and specific selection of the efficient enhancement methods. The orthorhombic pattern, with a very dense lipid organization, is the most prominent in human skin [42]. Taking into consideration that this field of research was established recently, this variability in results could be attributed to the lack of standardization of experimental configurations in different laboratories and the complexity of the multifactorial skin penetration process [49]. Experimental results are always related to the parameters tested in the experiment and the experimental configuration (ie, the results are individualized for each experiment). Nevertheless, overall generalized trends relating the physicochemical properties of nanoparticles to their behavior within the skin could be derived from the results of different experiments. Permeability coefficient and diffusion coefficient decreased by increasing the particle size. The study is indicative of size-dependent penetration of nanoparticles through the skin. This controversy may arise from differences in the integrity of the human skin samples used in the two studies. Another important parameter to be considered upon studying skin penetration of nanoparticles is their physical state while interacting with skin. Their aggregation probably arose from the exchange of citrate ions with skin proteins [45]. As the geometry of particles can affect their interactions with biological barriers [50,51], it may also have an effect on skin penetration. Moreover, they found that positively charged nanoparticles penetrate into human skin in higher numbers than their negatively charged counterparts, and attributed this to the favorable interaction of the positive moieties with the negatively charged skin. However, these arguments emphasize the necessity to optimize the surface charge of nanoparticles for efficient skin penetration. Another aspect to be considered when studying the effect of vehicles, especially organic solvent, is their potential toxicological hazards when humans are exposed to nanoparticles combined with solvents in research or industry [48]. However, a minor enhancement of nanoparticle penetration was detected after skin preincubation with toluene [45]. Thus, it is highly recommended to extend the research to more types of organic solvents. Among skin models, human skin is considered as the gold standard for penetration studies [40,49,53,54]. However, the ethical and availability limitations of human skin for research encouraged researchers to identify alternatives. Despite their general structural similarity to human skin, interspecies variability in barrier integrity does play a role [47,54]. Another significant difference between human and animal skin is the density of hair follicles, which could affect the deposition and penetration of nanoparticles. Importantly, in the latter condition, the decreased barrier function is a drawback to be considered. Apart from the origin of the skin model, both skin viability and integrity have key roles in penetration studies. Extending the research scope to find more alternative penetration models to human skin has recently received interest [46,56e58]. In this context, reconstructed skin equivalents have been developed by culturing keratinocytes and fibroblasts. Although the model might be useful for faster screening of the potential penetration of nanoparticles, further experiments are required to establish a relationship to human skin data [56]. Finally, it is important to select the skin model that gives relevant data and answers the questions posed. In in vitro permeation studies on full-thickness skin, the dermis could act as a reservoir that interacts with macromolecules or nanoparticles, hindering their permeation [53]. The model was a split-thickness skin (700 mm thick) that was prepared by removing much of the dermis. In any event, a well-designed experimental setup is very important for reliable results. Regarding experimental setup, a Franz diffusion cell is a commonly used device for penetration and permeation studies [15,43e45,48,53,59e62]. However, it exposes the skin to excessive pressure and shear stress that may affect the 106 8. Sometimes, another experimental configuration consisting of transwell plates is used, especially for less compact skin models such as mice skin [47] or skin equivalents [56]. Another important parameter is to preserve the condition and the integrity of the skin throughout the whole experimental time [47]. Typically, most in vitro permeation and penetration studies on human skin were terminated at 24 h [15,44,45,47,48,59,63e66], as this would be the maximum duration for which the skin maintains its structure. This time would vary for other skin models; for instance, the maximum time for newly born mouse skin to keep integrity was 6 h, as detected by histological examination [47]. In this technique, the mass content of elemental gold in nanoparticles is detected quantitatively [43,47,67]. However, these techniques give no idea about the spatial distribution of the particles within the skin [47]. Aspects to be taken into consideration for selecting the appropriate imaging techniques are the resolution and the ease of sample processing along with its influence on the tissue. A combination of more than one imaging technique would help to give complementary results for a better understanding of the penetration process. However, their signal strength may be less than that of fluorescent dyes or quantum dots [26]. Moreover, the compactness of the tissue and presence of wrinkles govern the maximum detection depth. For imaging, another important parameter is the resolution to individually distinguish single particles. Hence, for the detection of separate individual particles, measuring the intensity of the emitted light from the spot image can be considered [74]. The suitability of this method for nanoparticles imaging in skin might be questionable. In general, to avoid imaging problems regarding penetration into tissues, examination of skin longitudinal sections, though invasive, is an option. Nevertheless, skin sectioning is prone to the introduction of artifacts, and a possible depth change of nanoparticles could happen. In this context, a useful protocol might be cutting the skin longitudinally when it is perpendicular to the cutting blade to avoid the vertical translocation of the nanoparticles between the different skin layers [47,75]. The method relies on the conjugated simultaneous transmission and multiphoton imaging of longitudinal sections of skin. Images were then analyzed for the pixel frequency of the luminescent particles in the respective skin layers. Furthermore, the total pixel frequency was summed from all skin sections, and the weighed number of particles was calculated based on the resolution-limited spot size of a single particle to obtain a measure for the particles number [76]. The use of ultrasound as a mechanical penetration enhancement approach was previously accompanied with chemical enhancers [82e84] for a postulated synergistic effect. A research team led by Niidome has developed a surfactanteovalbuminegold nanorod complex (170. Chemical Penetration Enhancers Different classes of chemical compounds are used currently for enhancing skin penetration of active substances with different contributing mechanisms [77e79]. The influence of the different enhancers on the physical stability of the studied nanoparticles was also taken into consideration. Dermabrasion Dermabrasion is a well-known technique that is used for cosmetic purposes, where the surface layer of the skin is abraded. In addition, this technique can be used for absorption enhancement of drugs or nanoparticles through skin. In this regard, a study was conducted investigating the penetration and permeation of 12. The results showed that permeation in both cases was not statistically different, though skin penetration was more pronounced in the case of abraded skin [44]. This is also an indication of the nonabundant penetration pathway that could be related to pores or induced pores [10]. However, the intracellular pathway through the rigid corneocytes, which are actually dead cells filled with keratin and surrounded by an impermeable cornified envelope [14,42], is an unlikely pathway for nanoparticle diffusion. Generally, cell-penetrating peptides have the ability to enter cellular compartments by different mechanisms. The exact contributing mechanism for skin penetration enhancement is still unknown [92,93]. Alternatively, penetration through the transfollicular pathway is a particle sizeecontrolled process, where hair movement is claimed to pump the particles into the hair follicle [94]. A report indicated a size range of 400e700 nm for deep diffusion (compared to smaller or larger particles) through porcine hair follicles, which are similar to human hair follicles in size ratio [95]. In contrast, another report showed that 40 nm particles can diffuse deep through the hair follicles of human skin rather than larger particles (eg, 750 nm and 1. Regardless, skin appendages are of limited area compared to the total human skin surface area [93], so their contribution to particles penetration will be limited. They deliver their cargos to the Langerhans cells in the epidermis for the aim of transcutaneous immunization, or to the circulation through the capillaries located just below the epidermis. However, passive diffusion through the skin layers forming different biological barriers is difficult. Generally, for nanoparticle skin penetration, it is not a necessity that the particles reach the deeper skin layer intact [93,97]. Another important issue is the evaluation techniques for nanoparticles skin penetration. However, there are limitations in the currently used imaging techniques, either in depth monitoring or resolution issues, due to the complex structure of the skin. Consequently, validated skin alternatives for penetration should be developed, for instance skin equivalents from cultured skin cells. Nevertheless, results must still be processed with caution, especially when extrapolated to human data. For this reason, experimental results should be always accompanied with a full detailed description of the contributing factors. Moreover, the main goal of such experiments is to ensure and/or improve the health of humans whether by preventing hazards or developing drug delivery systems. Consequently, results of experiments, at which skin alternatives or skins of animals are used, would ideally be extrapolated to human data derived in the same laboratory. This in turn will help with the standardization of results and with judging the alternative experimental conditions and their appropriateness for the penetration studies. Furthermore, this will help to build up a database in each laboratory and hence lead to easier comparison between the results of experiments carried out in different laboratories under different conditions. Some parameters should be taken into account, for instance the maximum possible retention time of topical formulations on skin. Another important aspect that should be controlled during experiments is skin hydration. Ideally, skin seems not to allow for substantial passive penetration of particles even if they are very small (<10 nm). Studying and manipulating the different factors that could enhance skin penetration will allow researchers to reveal the underlying mechanism not known today. Specific targeting of the follicles might allow for relatively higher penetration.

In vivo studies comparing the bioavailability of anhydrous carbamazepine with its saccharin cocrystal showed that the cocrystal had the same chemical stability cholesterol hdl buy crestor american express, superior suspension stability hdl vs ldl cholesterol in eggs discount crestor master card, and bioavailability comparable to an immediate-release tablet (Hickey et al cholesterol average male order crestor visa. A glutaric acid cocrystal with a development compound (a potential sodium channel blocker) was shown to improve its bioavailability (MacNamara et al cholesterol ratio ideal order line crestor. As noted above cholesterol ratio of 3.4 crestor 5mg on line, cocrystals can contain more than two components cholesterol lowering through diet order discount crestor, and as an example Karki et al. In production, cocrystals have been produced by a variety of means, for example, dry grinding and solvent-assisted grinding are popular. Clearly, this approach will lend itself to high-throughput techniques and thus allow pharmaceutical scientists other options with respect to solid form selection. Solvates Solvates are materials where solvent or water molecules (in either stoichiometric or nonstoichiometric amounts) are incorporated in the crystal lattice or in interstitial voids or channels. It has been described by some authors by the term pseudopolymorphism; however, there has been some debate about whether this is the meaningful description and its use should now be avoided (Desiraju, 2004; Seddon, 2004). Generally speaking, four main roles are fulfilled by solvents in crystal structures (van der Sluis and Kroon, 1989). These are: (1) participation as acceptors and/or donors in hydrogen-bonding schemes, (2) filling void spaces, (3) completing coordination around metal ions, and (4) bridging polar and nonpolar regions in the crystal. Another type of inclusion solvate, known as clathrate, has been defined where the solvent is located in isolated lattice sites with no significant interaction to the host molecule; for example, Kemperman et al. By using this definition and a determination of the crystal structure, they showed that the material supplied as "warfarin sodium clathrate" (with 2-propanol) was in fact a solvate. Preformulation Investigations 55 If the crystal has large empty crystallographic channels or holes, their nature will determine which solvent will be included and the structure of the resulting solvate. From a structural point of view, the inclusion of a variety of solvates can show regularity. It should be noted that the crystal lattice can hold more than one solvent (heterosolvates). The remarkable capacity of sulfathiazole to incorporate solvent has been reported by Bingham et al. In this paper, it was claimed that sulfathiazole has the ability to form over 100 solvates, with over 60 crystal structures being solved. Structure property relationships were attempted, and the results indicated that a solvent containing an aromatic carbocyclic group did not give solvates, as did those solvents containing a hydroxy group, with the exception of n-propanol, which was unstable. Other solvents were incorporated into the crystal lattice, and on the basis of this study they proposed that two types of structure could be classified. These were (1) clathrates or inclusion phases, where the solvent fills space or is weakly H-bonded in the structure and (2) cocrystals, where the solvent is hydrogen bonded in the structure. Typically, solvates are formed at lower temperatures such that the temperature solubility curves will show temperature regions where solvates and unsolvated species are stable. The number of solvates that can be formed is a matter of experimentation, and clearly, high-throughput crystallization studies now yield many previously undiscovered solvates. If the solvate cannot be avoided from a process point of view, then it is important that solvates are desolvated before use. Typically, vacuum drying is used; however, it has been noted for several compounds that solvated alcohol can be removed more quickly by exposure of the solvate to water vapor (Pikal et al. However, in the case of warfarin sodium 2propanol solvate, this approach was found to be unsuccessful (Sheth et al. When this solvate was exposed, elevated relative humidities deliquescence took place, which did not change the underlying solvate structure. Associated with the desolvated solvate there may be residual solvent, which must be controlled. Perhaps a more direct and complete method of desolvation is to suspend the solvate in water. When the solvent is removed from the crystal lattice, which retains its three-dimensional order, a so-called isomorphic desolvate is created (Stephenson et al. The desolvated structure is highly energetic and reduces this situation by simply taking up moisture from the atmosphere or undergoing a certain degree of structural collapse to reduce the unit cell volume. The dihydrate 56 Steele and Austin and the tetrahydrofuran solvate lost their solvent anisotropically, which was followed by a cooperative structural rearrangement to an anhydrous polymorph. In contrast the dimethylformamide and dimethylsulfoxide solvates desolvated via a partial dissolution of the internal part of the crystals. Hydrates the most common case of solvation is the incorporation of water molecules, and they are almost always involved in hydrogen bonding. Indeed, it is the hydrogen-bonding network that contributes to the coherence of the crystal, such that they usually show, for example, slower dissolution rates compared with the corresponding anhydrates. As shown by Salameh and Taylor (2006), excipients can also have an effect on the stability of hydrates. A full understanding of the hydration state of compounds is not only important from a scientific perspective, it can also be important from an intellectual property point of view. This was exemplified by the case where a generic company, Apotex, which was successful in demonstrating noninfringement of the patent on paroxetine hydrochloride. This observation was attributed in part to the increase in free energy of the structure if solvents were included (as a result of loss of entropy by including solvent molecules), particularly if scope for favorable intermolecular interactions exists in the parent structure. The formation and occurrence of hydrates, as with all other processes, results from a fine thermodynamic balance, that is, compensation between enthalpy and entropy of the system. Generally, the formation of hydrates is governed by a net increase in favorable intermolecular interactions and the requirement of water is to satisfy specific roles to stabilize the crystal structure. Furthermore, the presence of water may serve to increase packing efficiency within the three-dimensional framework, thus maintaining a stable low-energy structure in accordance with the edict on the stability of the structure being related to density (Kitaigorodskii, 1961). By using the data from 3315 structures, they found that the two most common ways that water interacted was through the formation of three or four H-bonds with neighboring molecules. Statistically, they found the donor/ acceptor ratio and the molecular weight of the compounds, proposed earlier as factors, to be predictors of hydrate formation. Rather they found that the total polar surface increased the propensity for hydrate formation. For example, Hulme and Price (2007) were successful in predicting the structures within 5 kJ/mol of 5-azauracil monohydrate. Inclusion of water of crystallization can alter the free energy of a crystal structure and consequently, as with polymorphism, can have a profound impact on physicochemical properties such as solubility, dissolution (and hence bioavailability in the case of pharmaceuticals), and stability. An understanding of the properties and stability of hydrates relative to any parent anhydrate is important to rationalize material selection. Knowledge of the structural disposition to form hydrates would also impact on crystal-engineering developments. In instances for which water plays a crucial role in maintaining the crystal structure via the formation of a hydrogen-bonding network, dehydration can often lead to complete structural collapse, giving rise to an amorphous anhydrate, as observed with eprosartan mesylate dihydrate (Sheng et al. In this particular case, the water of crystallization forms a hydrogen-bonding framework directly to the parent drug and the salt counterion. Dehydration results in an amorphous material, which becomes annealed upon heating, giving rise to a crystalline hydrate. Such hydrates are considered to be very stable and represent developable materials. Hydrates in which water acts as a "space filler" occupying voids or crystallographic channels can dehydrate to give isomorphous anhydrates or undergo a change of structure to give a more densely packed arrangement. Generally, these types of hydrates are nonstoichiometric and the number of equivalent water molecules in the structure is directly related to the water activity (aw) in the surrounding environment. The geometry and size of the solvent channels in these structures can vary significantly from long, wide rigid structures that are maintained by a robust hydrogen-bonded framework to small interweaving arrangements for which the water may interact with the "host" structure. Dehydration from the long rigid channels results in minimal structural disruption and hence the resultant hydrate is structurally identical to the parent. In both cases however, the parent anhydrate is regarded as a hygroscopic material. Typically, this category of hydrates is regarded as less stable and less desirable as a developable material. Authelin (2005) has classified hydrates into two types, stoiochiometric and nonstoichiometric. By definition, stoichiometric hydrates, for example, mono-, di-, and trihydrates have well-defined moisture contents, and their crystal structures are different from the anhydrated form of the compound. Nonstoichiometric hydrates, on the other hand, exhibit a moisture content that is variable in nature. From a structural point of view, any uptake of water is usually accompanied by an anisotropic expansion of the crystal lattice. Further classifications of hydrates have been described by Morris (1999) and Vippagunta (2001). In this situation, the water molecules are not in contact with each other, that is, they are separated by the drug molecules. As can be surmised, the water molecules lie hydrogen bonded in channels and perform a space-filling role and are generally nonstoichiometric. Indeed, if water is not important to the stability of the crystal lattice, the structure may be the same as the parent hydrate, albeit with some crystal lattice contraction. The isomorphic structures are often very hygroscopic and rapidly rehydrate under ambient relative humidities. Class A: Desorption of the water molecules leads to collapse of lattice to yield an amorphous solid. Class B: Desorption and/or adsorption of water promotes transition to a new crystal form. Class C: As above, but the lattice expands to accommodate the water or contacts when it loses it. Cromolyn sodium is an example of this type of structure (Stephenson and Disroad, 2000). Class D: No significant change in the crystal structure takes place when water is adsorbed or desorbed. The water molecules occupy definite positions in lattice channels, but their interactions are rather weak in nature. A number of compounds have been reported to exhibit this type of behavior, for example, dirithromycin (Stephenson et al. This arises in the salts of weak acids, for example, calcium salts where the metal ion coordinates with the water molecules and is included in the growing lattice structure. These show both stoichiometric and nonstoichiometric behavior, for example Fenoprofen sodium is an example of a stoichometric hydrate (Stephenson and Disroad, 2000). In some structures, both (2) and (3) can occur together, for example, nedocromil sodium trihydrate (Freer et al. For example, amiloride hydrochloride dihydrate is present in two polymorphic forms. By milling or compressing both forms, it was shown that form A was more stable than form B. Niclosamide also exists as two monohydrated forms and an anhydrated phase (van Tonder et al. It was found that suspension formulations of the anhydrate readily converted to thick suspensions of monohydrate. Rapid solution-mediated conversion to a hydrate can often result in the formation of an unusable thixotropic formulation. In addition to this complication, in situ formation of a hydrated phase may modify dissolution and hence bioavailability of the material. For these reasons, it is important to assess the propensity for hydrate formation in formulation vehicles as part of the material selection program. The integrity of the suspension formulation showed a high degree of variability, with some aliquots of this formulation (when stored at subambient temperatures from a chemical stability perspective) giving rise to the formation of a thixotropic gel. The four forms were a pentahydrate, a trihydrate, and two others where the stoichiometry was determined to be 2. The hydration state of a hydrate depends on the aw in the crystallization medium, as shown by Zhu et al. However, the relative amount of water to water-miscible organic solvent is critical and is often only assessed in a semiempirical way. Polymorphic hydrates add a further complexity to the isolation procedure, as exemplified, for instance, by talterelin, a compound that exhibits two polymorphic forms of a tetrahydrate (Maruyama and Ooshima, 2000). Although the a-form of the compound showed good isolation behavior, the b-form was the thermodynamic stable form of the compound, especially in the presence of methanol. At 30% methanol, crystallization of the b-form dominated to the extent that it grew on the surface of the a-form. Amorphous Phases Amorphous phases are noncrystalline materials that possess no long-range order, but can exhibit a certain degree of short-range order (Yu, 2001; Bhugra and Pikal, 2008). Amorphous phases represent highly energetic, unstable materials largely because of this lack of threedimensional or long-range order found in crystalline materials. Such phases are termed X-ray amorphous and represent micro- or nanocrystalline structures. The amorphous phase can be thought of as a frozen or supercooled liquid, but with the thermal fluctuations present in a liquid frozen to a greater or lesser extent, leaving only largely static structural disorder (Elliot et al. Another way of viewing this situation is that the crystallinity can have a value that ranges from 100% for perfect crystals (0 entropy) to 0% (noncrystalline or amorphous); this is known as the one-state model. Yu (2001) has reviewed the characteristics and significance of the amorphous state with regard to pharmaceuticals. The amorphous state can be characterized by the glass transition temperature (Tg), where the molecular motion is faster above and slower below this transition (Zhou et al. The Tg can be thought of as similar to a second-order phase transition, but the glassy state is regarded as far from being in thermal equilibrium.

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