In order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous (i.v.) and non-intravenous administration. The absolute bioavailability is the dose-corrected area under curve (AUC) non-intravenous divided by AUC intravenous. Therefore, a drug given by the intravenous route will have an absolute bioavailability of 1 (F=1) while drugs given by other routes usually have an absolute bioavailability of less than one.

Relative bioavailability:

This measures the bioavailability of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route. When the standard consists of intravenously administered drug, this is known as absolute bioavailability.

REASONS OF POOR BIOAVAILABILITY¹:

1. Poor aqueous solubility:

Poor solubility of a drug is in most cases associated with poor bioavailability. The contents of gastrointestinal tract are aqueous and hence a drug having poor aqueous solubility has a low saturation solubility which is typically correlated with a low dissolution velocity, resulting in poor oral bioavailability.

2. Inappropriate partition coefficient:

Too hydrophilic drugs would not be able to permeate through the gastrointestinal mucosa and too lipophilic drug will not dissolve in the aqueous gastrointestinal contents. For optimum absorption, the drug should have sufficient aqueous solubility to dissolve in the gastrointestinal contents and also adequate lipid solubility to facilitate its partitioning into the lipoidal membrane and then into systemic circulation. Drugs having partition coefficient (log P) value in the range of 1 to 3 shows good passive absorption across lipid membranes, and those having log Ps greater than 3 or less than 1 have often poor transport characteristics.

3. First-pass metabolism:

Orally administered drugs must pass through the intestinal wall and then through the portal circulation to the liver; both are common sites of first pass metabolism (metabolism of a drug before it reaches systemic circulation). Thus, many drugs may be metabolized before adequate plasma concentrations are reached resulting in poor bioavailability.

4. Degradation in the gastrointestinal tract:

Drug substances used as pharmaceuticals have diverse molecular structures and are, therefore, prone to many and variable degradation pathways. Protein drugs, in particular are highly susceptible to inactivation due to the pH and the enzymes present in gastrointestinal tract. This degradation can be owing to the low pH in the stomach or due to chemical reactions taking place in the gastrointestinal tract, Enzymatic degradation of drug in gastrointestinal Tract or Interaction with food.

Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. With the progress in medicinal chemistry and, especially due to the recent introduction of combinatorial chemistry and high-throughput screening in identifying new chemical entities (NCE), the solubility of new drug molecules has decreased sharply. While a value of less than 20 μg/mL for the solubility of a NCE was practically unheard of until the 1980s, the situation has changed so much that in the present day drug candidates with intrinsic solubilities (solubility of neutral or unionized form) of less than 1 μg/mL are very common. More than 90% of drugs approved since 1995 have poor solubility. It is estimated that 40% of active new chemical entities (NCEs) identified in combinatorial screening programs employed by many pharmaceutical companies are poorly water soluble^2,5.

Molecules of this type can provide a number of challenges in pharmaceutical development and may potentially lead to slow dissolution in biological fluids, insufficient and inconsistent systemic exposure and consequent sub-optimal efficacy in patients, particularly when delivered via the oral route of administration. Approximately one-third of new compounds synthesized in medicinal chemistry laboratories have an aqueous solubility less than 10 μg/mL, another one-third have a solubility from 10 to 100 μg/mL, and the solubility of the remaining third is >100 μg/mL .

Advances in the pharmaceutical sciences have led to the establishment of a number of approaches for addressing the issues of low aqueous solubility. These strategies for improving and maximizing dissolution rate include micronisation to produce increased surface area for dissolution, the use of salt forms with enhanced dissolution profiles, solubilisation of drugs in co-solvents and micellar solutions, complexation with cyclodextrins and the use of lipidic systems for the delivery of lipophilic drugs. Although these techniques have been shown to be effective at enhancing oral bioavailability, the success of these approaches is dependent at times on the specific physicochemical nature of the molecules being studied^3,4.

A variety of formulation strategies have been developed to improve the solubility and, thus, the bioavailability of such compounds. Formulation strategies include self-dispersing and self-emulsifying formulations, solid solutions and dispersions, ionic inclusion and lipid-based complexation, formation of salts, polymorphs, cocrystals, and prodrugs, and particle size reduction techniques such as micronization or nanomilling. The techniques that are used to overcome poor drug solubility and hence bioavailability in turn can be broadly categorized under two major headings: chemical modifications and Physical modifications. Chemical modifications include techniques like – Salt formation, co-crystallization, Co-solvency, Hydrotropy, Use of solubilizing agent, Nanotechnology etc. whereas Physical modifications include techniques like-Particle size reduction (Micronization, nanosuspensions), Modification of Crystal habit (Polymorphs and Pseudopolymorphs), Complexation, Solubilization by surfactants (Microemulsions, SMEDDS), Drug dispersion in carriers etc⁵.

Solubilisation technologies such as micellar systems are reliant on the acceptable solubility and compatibility of therapeutic molecules in a limited range of pharmaceutically acceptable excipients, whilst the increasing number of weakly ionisable and neutral molecules entering development constrains the opportunities for salt formation as a method of improving dissolution rate. Furthermore, whilst micronisation increases the dissolution rate of drugs through increased surface area, it does not increase equilibrium solubility. Often for drugs with very low aqueous solubility, the achieved increase in dissolution rate is insufficient to provide adequate enhancement of bioavailability. The salt formation is not feasible for neutral compounds and the synthesis of appropriate salt forms of drugs that are weakly acidic or weakly basic may often not be practical⁴.

Much of the research that has been reported on solid dispersion technologies involves drugs that are poorly water-soluble and highly permeable to biological membranes as with these drugs dissolution is the rate limiting step to absorption. Hence, the hypothesis has been that the rate of absorption in vivo will be concurrently accelerated with an increase in the rate of drug dissolution. Physical modification has also been utilized to improve the solubility of poorly water soluble drugs. For such physical modifications, various excipients such as cyclodextrins, carbohydrates, hydro tropes, polyglycolized glycerides, and dendrimers are utilized⁶.

All the approaches used to counteract the solubility and bioavailability challenges, discussed above have some limitations. Nowadays numbers of advanced techniques have come up to solve these problems and the commercialization and scale-up has also been done in few of the cases.

Few such techniques have been discussed below:

1. Melt Sonocrystallization⁷:

Melt sonocrystallization a novel particle engineering technique to enhance dissolution of hydrophobic drugs and to study its effect on crystal properties of drug. Particle engineering techniques are developing to modify the physicochemical, micromeritic and biopharmaceutical properties of the drug. Number of particle design techniques are reported, such as spherical crystallization, extrusion spheronization, melt solidification, spray drying, pastillation, solution atomization and crystallization by sonication (SAXS), where simultaneous crystallization and agglomeration occur.

Ultrasound (US) was introduced in the traditional process of pharmaceutical technology of few years ago. For instance, several workers reported US assisted compaction and US spray congealing of variety of systems where physical modification of structure of drug or excipients was done to improve drug release and compaction properties of drug. Besides these effects on solid, US may also act on a liquid or melt mixtures causing cavitation and extreme molecular motion, which divides the drop of material into number of microdrops of narrow size range. One of the mechanical effects cause by ultrasonification is disaggregation or deagglomeration of the particle assembling. Cavitation is an important phenomenon of ultrasonication. The energy produced due to the collapse of bubbles at very high temperature was responsible for breaking of particles.

The so generated shock waves can cause the particle collide into one another with great force since these are similar charge particles problem of agglomeration is greatly reduced There are reports on application of ultrasonic (US) energy during crystallization, i.e. sonocrystallization. US energy has been used to achieve nucleation at moderate super saturation during the crystallization process or terminal treatment to achieve deagglomeration and to obtain desired crystal habit.

The drug with poor solubility is melted in a paraffin bath and the molten mass is poured in a vessel containing deionized water maintained in heated condition using thermostatic water bath and sonicated using probe ultrasonicator. The product obtained after solidification of dispersed droplet is separated by filtration and dried at room temperature.

Melt sonocrystallization, which is combination of melt solidification and ultrasonication, has advantages of melt solidified bonds and hard surface. This hardened surface has enabled the particles to withstand high sonication shear and maintain integrity even in highly porous form. Ultrasonication has been reported to cause spontaneous nucleation at relatively low degrees of super saturation, due to increase in number of collisions. Similarly, ultrasonication enhanced collisions in molecules of the melt favors nucleation rather than crystallization. Processing temperature is an important factor in the design of the technique.

Application of ultrasonic energy to the molten mass significantly increases kinetic energy of the molecules and number of collisions causing faster crystallization of the drug. Chaudhari P.D. et.al. have prepared and studied Valdecoxib agglomerates comprising of irregular in shape having rough surface with pores obtained by MSC technique, The MSC Valdecoxib agglomerate has shown some number of shallow circular pits on the surface, cracks in the crystals of the drug and has shown significantly higher specific surface area and thereby increase in saturated solubility.

2. Precipitation Ultrasonication Method^8,9:

The bioavailability of the solid API having poor aqueous solubility can be improved by formulating them as nanosuspensions. The dissolution rate of API is proportional to the surface area available for dissolution as described by the Noyes–Whitney equation and, in addition to the dissolution rate enhancement, an increase in the solubility of nanosized API is also expected. The nanocrystals can be obtained either by particle size reduction of larger crystals (top-down approach) such as high-pressure homogenization and media milling or by building up crystals by precipitation of dissolved molecules (bottom-up approach). Regarding the bottom-up method, in the last decade, supercritical fluid-based techniques have been widely investigated to obtain nanosized drug particles. In the last decade, ultrasound has received much attention and has been used as an effective method of controlling the nucleation and crystallization process. Ultrasound irradiation has been proved to be a feasible mixing method and it can intensify mass transfer and accelerate molecular diffusion.

In order to obtain crystals with an increased dissolution rate and, thus, to enhance the bioavailability, the particle size has to be reduced. Stable nanosuspensions were prepared by the precipitation–ultrasonication method. The process parameters that affect the process are concentration of API in the organic phase, the power input and the time length of ultrasonication.

For the preparation of nanosuspension of the API with poor aqueous solubility, the API is dissolved in organic solvent. PVA dissolved in water is used to obtain antisolvent as given in figure 1. Both the solutions are passed through a 0.45µm filter. The anti-solvent is cooled to below 3 ºC in an ice-water bath. Then, the organic solution is quickly introduced into the precooled anti-solvent with stirring at high speed. After the anti-solvent precipitation, the samples are immediately transferred to a test tube and treated with an ultrasonic probe at specific ultrasonic power input for specific time length.

Figure 1: Flow chart of the precipitation-ultrasonication procedure for the preparation of nanosuspension.

During the process, the temperature is controlled using an ice-water bath. The obtained nanosuspensions are concentrated by centrifugation at very high speeds using an ultracentrifuge. After the centrifugation, the supernatant is replaced with 0.2% PVA solution. The solid residue is redispersed using a bath sonicator and the final drug content is adjusted to required strength using an appropriate volume of 0.2% PVA solution.

Dengning Xia et.al. have prepared Nitrendipine nanosuspensions using the precipitation ultrasonication method. They found that particle size of nanocrystals was highly dependent on process parameters. With the optimized process parameters, nanosuspensions with diameter of about 209nm (±9 nm) could be obtained. No substantial crystalline change was found in nanocrystals compared with raw crystals. Marked enhancement of dissolution rate was achieved by the reduction in particle size. The oral bioavailability of Nitrendipine in Wistar rats resulted from nanosuspension was found to be increased by 5.0-fold compared with the commercial tablets. The advantage of this method being it is easy to apply and needs only simple equipment and, thus, is a promising method for preparing drug nanosuspensions.

3. LIQUISOLID Technique^10,11,12:

A liquisolid system has the ability to improve the dissolution properties of poorly water soluble drugs. Liquisolid compacts are flowing and compactable powdered forms of liquid medications. Several studies have shown that the liquisolid technique is a promising method for promoting dissolution rate of poorly water soluble drugs. In liquisolid compact, a liquid medication is converted into acceptably flowing and compactible powder forms. The term ‘liquid medication’ implies liquid lipophilic (oily) drug and solution or suspension of poorly water soluble drugs carried in suitable water miscible non-volatile liquid systems termed the liquid vehicle. By simple blending with suitable excipients ‘carrier and coating materials’, the liquid medication may be converted into a dry-looking, non-adherent, free flowing and readily compactible powder.

Since drug dissolution is often the rate limiting step in gastrointestinal absorption, the significant increase in wetting properties and surface area of drug particles available for dissolution from liquisolid compacts may be expected to display enhanced drug release characteristics and, consequently, improved oral bioavailability. The technique of liquisolid compacts has been successfully employed to improve the in vitro release of poorly water soluble drugs such as Carbamazepine, Famotidine, Piroxicam, Indomethacin, Hydrocortisone, Naproxen and Prednisolone etc.

The drugs which are water insoluble or liquid lipophilic are dissolved in a suitable selected non-volatile solvent. This non-volatile solvent with drug dissolved may exist either in solution or else suspension form known as “liquid medicament”. The liquid medicament is converted into free flowing, non-adherent, dry form and readily compressible powders with the help of different compressible carriers like (Starch, cellulose and lactose etc.) and other coating materials like (Colloidal silica and Talc etc.). Because of drug being present in the liquid medicament as solubilized or molecularly dispersed state, the dissolution is enhanced due to increased surface area as well as wetting area. There by the Liquisolid technique is applied for water insoluble drugs to enhance dissolution rate, it may also increase bioavailability in turn.

4. Nanocrystal technology:

The pharmaceutical benefits of nanocrystals include improvement in formulation performance, such as enhanced dissolution velocity and saturation solubility, reproducibility of oral absorption, improved dose-bioavailability, proportionality and increased patient compliance via reduction of number of oral units to be taken. Nanocrystal serves as ideal delivery system for oral drugs having the dissolution velocity as rate limiting step for absorption, i.e. drugs of the biopharmaceutical classification system (BCS) class II and IV. In addition, nanocrystals can be injected intravenously as aqueous nanosuspensions.

Two basic approaches are involved in production of nanocrystals, the bottom–up technologies (controlled precipitation/ crystallization) and the top–down technologies, nanonizing (large-size drug powder to be reduced in size, e.g. by mechanical attrition).

4.1 Bottom-up techniques^13,14,15:

Around 1980 Sucker developed the so called “hydrosols”, the intellectual property acquired by Sandoz (nowadays Novartis). This technology is basically a classical precipitation process where drug is dissolved in a solvent and subsequently precipitated by mixing with a non-solvent. It yields crystalline drug nanoparticles. This method requires strict control of the process, avoidance of crystal growth (to the micrometer range), drug solubility in at least one solvent, and of course has the problem of solvent residues.

Another precipitation process was developed by Auweter and Horn, leading to amorphous nanoparticles of the active. The particles are spherical due to precipitation process. This process is used by BASF for products developed in the food sector (e.g. Lucarotin® or Lucantin® which is a solution of the carotenoid, together with a surfactant in a digestible oil), and for pharmaceuticals by Soliqs® (AbbottGmbHandCo. KG, Ludwigshafen) previously Knoll/BASF. The Soliqs trade name is NanoMorph®.

4.2 Top-down techniques:

(a) NanoCrystals® technology^[16,17]:

The NanoCrystals® technology by élan (prev. Nanosystems) uses a bead/pearl mill to achieve particle size diminution. It was developed by Liversidge et al. Milling media, dispersion medium (generally water) containing stabilizer along with drug are charged into a milling chamber. Shear forces generated by the movement of the milling media lead to particle size reduction. Smaller or larger coated milling pearls of ceramics (cerium or yttrium stabilized zirconium dioxide), stainless steel, glass or highly crosslinked polystyrene resin-coated beads can be used. Erosion from the milling material during the milling process is a common problem of this technology. The milling time mainly depends on the hardness of the drug, viscosity, temperature, energy input, size of the milling media and surfactant concentration used. The milling time can last from about 30 min to hours or several days. This is an important industrially used technology for particle size reduction, proven by the FDA-approved products.

Lab scale production can be carried out at using 100mg or less of API by using the Nanomill® system (élan Drug Discovery, PA, USA). The chemical form of API needs to be considered for laboratory testing, typically the neutral form is preferred. Production volumes of more than 5 L (flow through mode) can be produced using the Dynomill (Glen Mills, Inc. Cliffton, NJ, USA) with chamber size of 300 and 600 mL. Also larger sized mills are available (e.g. Netzsch mills (Netzsch Inc., Exton, PA, USA)), e.g. in 2, 10 and 60 L chamber size.

(b) Microfluidizer technology (IDD-P^TM technology)¹⁸:

The Microfluidizer technology is based on the jet stream principle and can generate small particles by a frontal collision of two fluid streams in a Y-type or Z-type chamber under pressures up to 1700 bar.

Figure 2: Working of Microfluidizer processor

The jet streams lead to particle collision, shear forces and cavitation forces (Microfluidizer®, Microfluidics Inc.). working of Microfluidizer processor is shown in figure 2. Often a relatively high number of cycles (50–100 passes) are necessary to obtain sufficient particle size reduction. SkyePharma Canada Inc. (formerly Canadian company Research Triangle pharmaceuticals (RTP)) uses this principle for their Insoluble Drug Delivery-Particles (IDD-PTM) technology to achieve the production of submicron particles of poorly soluble drugs. Product on the market is Triglide®, fenofibrate.

(c) Dissocubes® technology^19-28:

The Dissocubes® technology was developed by Müller and co-workers by employing piston-gap homogenizers (e.g. APV Gaulin/Rannie homogenizers). The technology was acquired by SkyePharma PLC in 1999. A drug dispersed in an aqueous surfactant solution (macrosuspension) is forced by a piston under pressure (up to 4000 bar, typically 1500–2000 bars) through a tiny gap (e.g.5–20µm). The resulting high streaming velocity of the suspension causes an increase in the dynamic pressure. This is compensated by a reduction in the static pressure below the vapor pressure of the aqueous phase; hence, water starts boiling forming gas bubbles. These gas bubbles collapse immediately when the liquid leaves the homogenization gap (=cavitation). The drug particles are reduced in size due the high power of the shockwaves caused by cavitation. The mean size of bulk population obtained for the high pressure homogenization process depends on the power density of the homogenizer (homogenizer pressure), number of homogenization cycles and hardness of drug. Because of crystalline nature they appeared in cuboid or irregular shape, in contrast to spherical amorphous drug nanoparticles.

(d) Nanopure® technology²¹:

The Nanopure® technology is another approach using the piston-gap homogenizer (prev. PharmaSol GmbH, now Abbott). This technology uses a primary dispersion medium, non-aqueous liquids, e.g. oils, liquid and solid (melted) PEG, or water reduced media (e.g. glycerol–water, ethanol–water mixtures), and optionally homogenization at low temperatures. These media have low vapor pressure, cavitation takes place very limited or not at all. At homogenization at room temperature, the water starts boiling, i.e. the static pressure on the water is reduced to the vapor pressure of water at 20 ◦C, being 23.4. For example, the vapor pressure of Miglyol 812 oil is only 0.01 hPa (=0.01 mbar) at 20 ◦C, i.e. more than 2000 fold lower. Therefore when water shows cavitation, the oil will not. Even without cavitation, the size diminution is sufficient because of shear forces, particle collisions and turbulences. The optional low temperatures allow the processing of temperature sensitive drugs, in addition at lower temperatures materials, are more fragile. Final nanosuspensions product in oil or PEG can be directly filled into gelatin or HPMC capsules.

With nanopure technology, homogenization can be performed in a nonaqueous phase or phases with reduced water content. And, in contrast to more pronounced cavitation at higher temperatures, homogenization is similar or more efficient at lower temperatures, even below the freezing point of water.

(e) NANOEDGE^TM technology^3,21:

This is a type of combination technology where a combination of a pre-treatment step with a subsequent high energy steps, for example – but not necessarily – high pressure homogenization is done. The NANOEDGE^TM technology by Baxter uses a first classical precipitation step with a subsequent annealing step by applying high energy, e.g. high pressure homogenization. According to the patent claims, the annealing step prevents the growth of the precipitated nanocrystals. Annealing is defined in this invention as the process of converting matter that is thermodynamically unstable into a more stable form by single or repeated application of energy (direct heat or mechanical stress), followed by thermal relaxation. This lowering of energy may be achieved by conversion of the solid form from a less ordered to a more ordered lattice structure. Alternatively, this stabilization may occur by a reordering of the surfactant molecules at the solid–liquid interface.

The technique is based on direct homogenization, microprecipitation, and lipid emulsions. In microprecipitation, the drug first is dissolved in a water-miscible solvent to form a solution. Then, the solution is mixed with a second solvent to form a presuspension and energy is added to the presuspension to form particles having an average effective particle size of 400 nm to 2 μ. The energy-addition step involves adding energy through sonication, homogenization, countercurrent flow homogenization, microfluidization, or other methods of providing impact, shear, or cavitation forces. A drug suspension resulting from these processes may be administered directly as an injectable solution, provided water-for-injection is used in the formulation and an appropriate means for solution sterilization is applied. Nanoedge technology facilitates small particle sizes (<1000 nm [volume weighted mean]), high drug loading (10–200 mg/mL), long-term stability (up to 2 years at room temperature or temperatures as low as 5 °C), the elimination of co solvents, reduced levels of surfactants, and the use of safe, well-tolerated surfactants.

(f) SmartCrystal® technology:

The smartCrystal® technology is owned by Abbott and marketed by its drug delivery company Soliqs in Ludwigshafen/Germany. It is a family of various combination processes, a kind of tool boxes to tailor-make the nanocrystals for each specific application, and considering the physical properties of the drug (e.g. hardness). It was acquired from PharmaSol GmbH in 2007, and these crystalline nanoparticles complement to the amorphous nanoparticles by Soliqs, NanoMorph®. The smartCrystal technology is considered as the second generation of drug nanocrystals. Injecting nanosuspensions with very small nanocrystals can permit fast dissolution and mimic injection of a solution.

5. Biorise® Technology^[^29]:

Eurand’s Biorise technology exploits the much faster dissolution rate of nanocrystalline and amorphous forms of drugs when compared to unmodified or even micronized forms. As shown in figure 3 Biorise creates new physical entities (NPEs) by physically breaking down a drug’s crystal lattice, resulting in drug nanocrystals or amorphous drug with enhanced solubilization properties, faster absorption and ultimately, increased absolute bioavailability. These NPEs are then stabilized in an inert biological carrier, generally a polymer, to prevent the processed drug from agglomerating or reverting back to its crystalline form.

Figure 3: Biorise Technology

Eurand has two alternative activation systems available that are used to convert a drug into its thermodynamically activated state. These systems provide flexibility and allow the technology to be applied to a range of compounds with differing characteristics:

1. High Energy Mechanochemical Activation (HEMA):

This involves the application of friction and impact energy to the drug, thereby increasing its entropy and transforming the drug into its activated state. This is a dry system, which maintains the drug/carrier matrix in a powder form at all times.

2. Solvent Induced Activation (SIA):

This technique is particularly suitable for thermolabile compounds and compounds with a low melting point. With this system, a drug can be solubilized in an appropriate solvent and layered on to swellable, crosslinked carriers. Controlled evaporation of the solvent and drying of the material creates nanoparticle and amorphous drug that are stabilized in a carrier. Compared to other solubility enhancing technologies, Eurands’ Biorise system offers faster and more efficient processing times, is cost effective, and produces a stable product without the use of surfactants. The finished product is a drug powder, which can be incorporate into a variety of dosage forms including tablets and capsules.

6. Diffucaps® Technology²⁹:

Eurand’s Diffucaps technology (figure 4) is a flexible multiparticulate system that provides optimal release profiles for single drugs and drug combinations to reliably overcome the problems associated with pH-dependent insolubility encountered in the GI tract. This proprietary technology has been developed specifically for weak, basic drugs and involves the incorporation of pharmaceutically acceptable organic acid or a crystallization-inhibiting polymer onto inert cores and coating the drug-layered beads with proprietary functional polymers.

Figure 4: Diffucaps Technology

Formulations using an acid core ensure an acidic environment surrounds the drug at all times, thereby producing a soluble drug in an in vivo environment where it would otherwise be insoluble. Further, Diffucaps incorporates release-controlling polymers, a functional drug layer, core granules or crystals, and a protective coating in one technology, providing sophisticated control of drug delivery timing that goes beyond what a single technology system can provide. Drug beads are typically created by layering active drug onto a neutral core (such as sugar spheres or cellulose spheres) and applying one or more rate-controlling, functional membranes. The drug layering process can be conducted either from aqueous or organic solvent-based drug solutions/suspensions and results in a small (approximately 1.5 mm or less in diameter), spherical, and multilayered bead particle. The beads may then be filled into capsules or compressed into orally disintegrating tablets to create the final dosage form. The inherent flexibility of the Diffucaps system permits the easy adjustment of both dosage strength and pharmacokinetic profile to achieve the required in vivo results. Beads can have different release profiles, different active ingredients, or both – all in one product.

7. Oral synchronous drug delivery system ^{[30] :}

Delivery Therapeutics Ltd (DT), an Israeli biotechnology company, has developed a proprietary technology enabling an efficient oral delivery of poorly absorbed drugs, mainly protein drugs and poorly-water soluble drugs. It is a novel approach to increase the bioavailability of protein drugs, poorly absorbed drugs and drugs susceptible to efflux pumping incidents. This approach has been tested over 4 years in a variety of biological models and resulted in the design of the oral synchronous delivery system (OSD).

The OSD proprietary (patent allowed in Israel, patent pending in the USA) matrix is a tailor-made platform, capable of synchronizing the release process of drug(s) together with functional additives such as absorption enhancers (AE); enzyme inhibitors (PI), and efflux pump inhibitors [e.g. p-glycoprotein (pGP)], over a predetermined time interval along specific locations in the intestine. In other words: the matrix is designed to cause a concomitant release of two ingredients or more and “forces” them to stay together, while traveling down the gut. The concomitant release provided by the OSD allows continuous action of the functional adjuvant (absorption enhancer, enzyme inhibitor, or solubilizing agent) throughout the whole length of the intestine, or at pre-designed intestinal segments over predetermined time slots. The outcome is an improved bioavailability of the drug of interest compared with the bioavailability accomplished when administered in non-synchronous carriers (Figure 5 below).

Figure 5: concept of Oral synchronous drug delivery system

8. Cryogenic processing techniques:

8.1 Spray freezing into liquid(SFL)^31-34:

Cryogenic processing techniques have been developed to enhance the dissolution rate by creating nanostructured amorphous particles with high degrees of porosity. The cryogenic spray-freezing into liquid (SFL) process produces amorphous solid solutions of drug and excipients. The formation of metastable amorphous solid solutions yields higher energy states for the drug and thus a greater thermodynamic driving force for dissolution.

Figure 6: Schematic diagram of the SFL apparatus illustrating the solution cell (A), high pressure pump (B), atomizing nozzle (C), and the cryogenic liquid cell (D).

SFL technology is a cryogenic particle engineering process that utilizes the atomization of a feed solution containing APIs and/or excipient(s) directly into a cryogenic liquid to produce frozen nanostructured particles. The frozen particles are then lyophilized to obtain dry, free flowing micronized powders. Advantages of the SFL process result from intense atomization in conjunction with rapid freezing rates. Because liquid–liquid impingement occurs between the pressurized feed solution exiting the nozzle and the cryogenic liquid, such as liquid nitrogen, the highest degree of atomization is achieved by spraying directly into the cryogenic liquid as opposed to spraying into the vapor phase above the cryogenic liquid.

SFL particles have been shown to have a large specific surface area, producing powders with rapid dissolution. Additionally, the SFL process produces powders that are consistent with a solid solution.SFL powders are formulated with small amounts of surfactant to achieve high drug loadings (50%-86% drug/total solids) while maintaining high dissolution rates. SFL powders require smaller amounts of surfactant to achieve high dissolution rates.These high-drug-loaded SFL powders contain amorphous nanostructured aggregates with high surface area and excellent wettability. A schematic diagram of the SFL apparatus is shown in figure 6.

8.2 Spray freeze drying:

Another cryogenic process, the spray-freeze-drying (SFD) method, typically involves the atomization of a drug-containing solution in gaseous nitrogen above a pool of liquid nitrogen. The fine droplets of drug/solvent are frozen, then lyophilized to remove the solvent. The rapid freezing rates in the cryogenic liquid substrate do not allow for molecular arrangement into crystalline domains, so SFD processing produces amorphous drug nanoparticle aggregates with improved dissolution rates.The scalability of this type of technology, however, has limited its widespread industrial use.

8.3 Ultra-rapid Freezing (URF)³⁵:

Ultra-rapid freezing (URF) technology involves the use of a solid cryogenic substrate with a thermal conductivity between 10 and 20 W/m degrees K. A solution of the drug is applied to the solid surface of the substrate, where instantaneous freezing takes place. Brownian motion of the particles in solution is slowed significantly, so reactive species have little time to react before being frozen into the solid state. Removal of the frozen particles and lyophilization of the solvent produces stable amorphous drug particles. URF technology has been shown to produce uniform, amorphous, drug particle/excipient aggregates.Additionally, the process is continuous, allowing for improved scale-up applications. A reservoir of boiling cryogenic liquid is not required, allowing for lower operating costs and more convenient operation.

Numerous citations report solvent/drug/excipient compositions being frozen in liquid or gaseous nitrogen or other cryogenic fluids. All of these approaches face the same challenge in transferring the heat necessary to cool and freeze the solution forming the drug particle domains. The heat transfer is forced to pass through a gas film at the surface of the particle. This imparts a rate-limiting step in the heat transfer and defines the maximum freeze rate.

URF technology overcomes the limitation of transferring heat through a gas film by eliminating the gas interface element and using direct contact with the cryogenic substrate. Drug solutions that come into direct contact with a boiling liquid cryogenic substrate transfer heat through a gas bubble film until the temperature of the particle comes into thermal equilibrium with the liquid at its boiling point.Note that conduction is improved by using a cryogenic material with a high thermal conductivity, density, and mass relative to the solution being frozen so as to maintain the surface temperature and heat transfer rate while the solution is being frozen. With URF technology, the thickness of the freezing solution may be controlled to fix its minimum freezing rate since the freezing rate drives the particle formation and determines the freezing solution's characteristics and, hence, drug particle formation.

Purvis T et.al. prepared rapidly dissolving formulations of the poorly water-soluble drug Repaglinide using ultra-rapid freezing (URF). URF processing created nanostructured drug/excipient particles with higher dissolution rates than were achieved for unprocessed drug. It was found that URF processing, yielded fast-dissolving formulation that was physically and chemically stable, resistant to alkali degradation or spontaneous recrystallization in the formulation.

CONCLUSION:

Poor bioavailability is a major limitation in successful drug delivery by oral route. It is rapidly becoming the leading hurdle for formulation scientists working on oral delivery of drugs. Lot of research work is focused on oral bioavailability enhancement of the poorly absorbed drugs. Growing percentage of NCEs displaying solubility issues demands that technologies for enhancing drug solubility be developed to reduce the percentage of poorly soluble drug candidates eliminated from development as a result. Drug cyclodextrin inclusion complexes, surfactant addition and particle size reduction via comminution, spray drying and solvent recrystallisation, possess significant limitations on the extent to which they may solubilise insoluble and nearly insoluble compounds. Novel technologies, such as sonocrystallisation, nanotechnologies such as nanosuspension, nanoemulsion, spray freezing in to liquid and some commercialized technologies such as nanocrystal, nanopure, nanoedge, biorise®, diffucaps® etc. present novel methods of solubilisation that may allow for greater opportunities to deliver poorly soluble drugs.

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Received on 17.08.2011

Accepted on 15.09.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(5): Sept.-Oct. 2011, 183-192

Trade name	Therapeutic use	Applied technology	Pharma company
Rapamune® (Rapamycin, Sirolimus)	Immunosuppressive	élan nanosystems	Wyeth Pharmaceuticals
Emend® (Aprepitant)	Antiemetic	élan nanosystems	Merck and Co.
Tricor® (Fenofibrate)	Hypercholesterolemia	élan nanosystems	Abbott Laboratories
Triglide® (Fenofibrate)	Hypercholesterolemia	IDD-P® technology	Produced by SkyePharma marketed by Sciele Pharma Inc. (Atlanta, CA, USA).
Megace ES® (Megestrol acetate)	Antianorexic	élan nanosystems	Par Pharmaceutical Companies Inc. (Spring Valley, NY, USA)
Avinza® (Morphine sulfate)	Psychostimulant	élan nanosystems	King Pharmaceuticals
Focalin® XR (Dexmethyl-phenidate HCl)	Psychostimulant	élan nanosystems	Novartis
Ritalin® LA (Methylphenidate HCl)	Psychostimulant	élan nanosystems	Novartis
Zanaflex CapsulesTM (Tizanidine HCl)	Muscle relaxant	élan nanosystems	Acorda