Compact Tablets Research Articles

Direct compression of diclofenac sodium tablet using modified Musa paradisiaca pseudostem cellulose-corn starch polymer alloy

Background: Biomaterials exhibit different functional properties. The aim of this study is to formulate direct compressible diclofenac sodium tablet using modified pseudostem cellulose and starch complex. Methods: Cellulose was extracted from Musa paradisiaca pseudostem and modified using acid-hydrolysis and fermentation techniques. The modified cellulose was evaluated using FT-IR analysis. Avicel pH-101 was used as control cellulose. Micromeritic properties of the modified cellulose were evaluated using tapped consolidation technique. Co-milling heat technique was used to produce polymer-alloy of 21.7, 43.4 or 87.0% of modified cellulose and 78.3, 56.6, or 13.0% dried corn starch respectively. The dried starch or polymer-alloy was blended with diclofenac sodium, co-povidone and magnesium stearate to produce batches A - G. The blends were analyzed for Kawakita densification properties before being compressed to tablets. The physicochemical and drug-release properties of the tablets were evaluated. Results: Of the dried pseudostem mass, 52.01% and 48.04% of extracted and modified celluloses respectively were obtained. The FTIR study showed presence of cellulose in the pseudostem extract and no interaction between the cellulose and diclofenac sodium. The celluloses had Hausner’s ratios < 1.32 and Carr’s indices < 23.54%. The polymer-alloy blends showed Kawakita compressibility < 16.34 and compactibility > 489.30. The control tablets passed physicochemical properties tests. The test tablets had hardness > 12.34 KgF, disintegration time > 144.67 min, and released 7.64 - 77.59% drug in acidic to basic medium over 240 min. The result indicates that the pseudostem-cellulose was flow-able, and produced compactible polymer alloys and extended drug-release tablets. Conclusion: Direct compression of diclofenac sodium with Musa paradisiaca pseudostem cellulose-corn starch polymer-alloy produced compact tablets with extended drug release. Keywords: Acid-hydrolysis, co-milling, compressibility, drug release

Quality-by-Design-Based Development of Rivaroxaban-Loaded Liquisolid Compact Tablets with Improved Biopharmaceutical Attributes.

Rivaroxaban (RXN) finds use in the management of pulmonary embolism and deep vein thrombosis. Its poor solubility (5-7µg/mL) and P-gp-mediated efflux from intestinal lining limits the oral application of RXN. This work assessed the impact of liquisolid compact technique in augmenting the solubility and bioavailability of RXN. PEG 400, Avicel PH 200, and Aerosil 200 were used as non-volatile liquid, carrier, and coating material, respectively, to formulate RXN liquid-solid compacts (RXN LSCs). A 32-factor factorial design was used in the optimisation to assess the impacts of factors (load factor and carrier:coating ratio) on the responses (angle of repose and Q30 min). Pre-compression parameters of RXN LSCs suggested adequate flow and compressibility. Optimisation data suggested significant influence of factors on both the responses. Optimised RXN LSC-based tablets showed a significantly higher in vitro dissolution rate than RXN API and Xarelto® tablets due to improved solubility, reduced crystallinity, greater surface area, and enhanced wetting of RXN particles. XRD, DSC, and SEM data supported RXN's amorphization. The cytotoxicity (MTT assay) and permeation studies indicated the nontoxicity of prepared RXN LSC tablets and the role of PEG 400 in inhibiting P-gp. Pharmacokinetic study of RXN LSC-based tablets in Albino Wistar rats exhibited 2.51- and 1.66-times higher AUC in comparison to RXN API and Xarelto® tablets respectively, demonstrating that developed formulation had a greater oral bioavailability. The RXN LSC tablets showed longer bleeding times and higher rates of platelet aggregation than RXN API. Thus, RXN LSC tablets can be considered a facile, scalable technology.

Effect of co-processed excipient type on properties of orodispersible tablets containing captopril, tramadol, and domperidone

An important feature of orodispersible tablets (ODTs) is the convenient administration of the drugs, in some cases, faster onset of action, stability maintenance, and dose precision. This work focused on the preparation of ODTs containing mannitol-based co-processed excipients Prosolv® ODT G2, Ludiflash® and Parteck® ODT in combination with tramadol, captopril, and domperidone by direct compression.Prosolv® ODT G2 showed high energy of plastic deformation due to the content of microcrystalline cellulose. Parteck® ODT provided compact tablets due to the content of granulated mannitol. All drugs decreased tensile strength, increased friability, prolonged disintegration time, and decreased the porosity of tablets. Tablets containing Prosolv® ODT G2 with captopril, domperidone, and tramadol; and Parteck® ODT with domperidone met the requirements for ODTs production, i.e., friability ≤ 1% and disintegration time ≤ 180 s, fast wetting time, high water absorption ratio, and adequate tensile strength. The disintegration time was tested using both the pharmacopeial method and the BJKSN-13 apparatus. The results indicate the significant difference between these methods, with the disintegration time being longer when tested with the BJKSN-13 instrument.

Study on the properties of Ca9Co12O28 under high pressure

The pure Ca 9 Co 12 O 28 thermoelectric (TE) material powder is synthesized by solid state sintering method. The powder is pressed into compact tablets under pressure of 200 MPa, 2.0 GPa, 2.5 GPa, 3.0 GPa, 3.5 GPa and 4.0 GPa, respectively. The electrical conductivity, Seebeck coefficient, thermal conductivity and hardness are tested. The properties of specimens under different high pressures are compared and analyzed. It is found that the relative density of the specimens under different high pressures can reach 95% approximately. The highest power factor of the specimens is 2.171μW/(cm·K 2 ) at 3.5 GPa, which is 2.4 times that at 200 MPa. At the same time, the maximum Vickers hardness of the specimens under 3.5 GPa is 127.7 MPa, while that under 200 MPa is only 16.8 MPa, indicating that the hardness under 3.5Gpa is increased by about 6.6 times. More importantly, it is found that the thermal conductivity of the specimens decreases with pressure in the range of 2.5Gpa–4.0Gpa, which proves that high pressure can refine the heat transfer performance effectively. This study lays the foundation for the synthesis of new-type Ca 9 Co 12 O 28 TE materials with high machinability, high power factor, low thermal conductivity and high TE figure of merit with high-pressure technology.

Improvement of The Photostability of Nimodipine by Using Liquisolid Compacts Technique

Liquisolid compacts are one of the modern drug formulation techniques used for drug formulation for several objectives including protection against photosensitivity. This study evaluates the photoprotective effect of the liquisolid compact technique on a calcium channel blocker antihypertensive drug, nimodipine, which is considered a photosensitive drug model. Liquisolid compact tablets of nimodipine were prepared from; Avicel PH-102 as a carrier material, (colloidal silicon dioxide, Cab-O-sil, and titanium dioxide as coating materials), croscarmellose sodium (CSS), sodium starch glycolate (SSG), crospovidone (CP) as super disintegrants, and propylene glycol as the liquid vehicle. However, the ratio of carrier to coating materials was kept constant in all formulations at 35:1. This ratio was chosen after testing the ratios 15:1, 20:1, 25:1, 30:1 and 35:1. The feasibility of the prepared liquisolid systems was also evaluated for first; the pre-compression and post-compression characteristics. Second, the possible drug-excipients interaction using FT-IR. Third, the photostability of Nimodipine in pure form, conventional tablets, and in the prepared liquisolid tablets through irradiation with a light dose of 0.55 W/m2/h visible light, 50 W/m2/h UVA and 0.27 W/m2/h UVB for 12 h in order to estimate the effect of coating material type on Nimodipine stability especially in the prepared liquisolid formulations. The results showed that all of the prepared liquisolid tablets showed satisfactory properties regarding pre and post-compression properties. Interestingly, the FTIR spectra study ruled out any interaction between nimodipine and excipients in the prepared liquisolid tablets. Besides, all of the prepared liquisolid tablets had shown a superior drug dissolution profile compared to the conventional and direct compressed tablets. Finally, 92.43% of the drug remaining was found in the liquisolid formulation (F7) after 12 h photo-irradiation as compared to 65.48% drug remaining for the pure drug substance and 75.12% for directly compressed tablets indicating that liquisolid technique had significantly inhibited the photo-degradative effect of light in the prepared liquisolid formulations. It can be concluded that the liquisolid compacts technique is a promising approach for the improvement of photostability of this photosensitive Nimodipine with an acceptable stability as well as enhanced dissolution rate.

Discriminating polymorph distributions in pharmaceutical tablets using stimulated Raman scattering microscopy

AbstractStimulated Raman scattering (SRS) imaging is used to probe active pharmaceutical ingredient exhibiting polymorphism within compact tablets. We show that few SRS images performed at selected wavenumbers allow to access both active pharmaceutical ingredients polymorphs and excipients from which molecular mapping is retrieved over millimetre‐size areas. We exemplified the approach using SRS images acquired at five wavenumbers to map clopidogrel and amibegron polymorphs embedded into excipients (polyethylene glycol, corn starch, and mannitol tablets). Our study demonstrates that SRS imaging can be used as a novel fast molecular mapping technique for pharmaceutical tablets characterization.

Quality-by-Design based development and characterization of pioglitazone loaded liquisolid compact tablets with improved biopharmaceutical attributes

The present research work describes the formulation development of liquisolid compact tablets of pioglitazone for improving its dissolution performance and antidiabetic activity. Using Quality by Design (QbD) approach, a total of nine formulations were prepared as per the central composite design (CCD) by selecting colloidal silicon dioxide and microcrystalline cellulose as independent, while polyethylene glycol 400 was used as non-volatile solvent. The formulations were evaluated for Carr's index and disintegration time as the dependant variables. Kawakita and Heckel analysis carried out on the liquisolid compacts indicated dense nature of the particles along with good compaction characteristics. Aerosil 200 and microcrystalline cellulose showed plastic deformation suggesting improved compressibility. Moreover, the liquisolid compact tablets exhibited faster rate and extent of drug release than the directly compressed tablet. In vivo pharmacodynamic study performed on normal and diabetic male Swiss albino mice confirmed that optimized liquisolid compact tablet formulation showed better reduction of blood glucose level as compared to directly compressible tablet and pure drug. In a nutshell, the present work successfully construed that liquisolid compact technique can be a novel approach for improving dissolution performance of pioglitazone in potentiating its antidiabetic activity.

Choosing the Right Laser for Microelectronic Packaging Tasks

AbstractThe size of semiconductor dies and packaged devices continues to shrink in order to support more sophisticated and compact tablets, phones, watches and other wearables. This trend creates greater opportunities for lasers because of their unique ability to perform diverse materials processing tasks with high precision and minimal heat‐affected zone (HAZ). As a result, lasers are finding increased use in wafer dicing, package singulation, optical debonding, micro‐via drilling, RDL (re‐distribution layer) structuring, dicing tape cutting (EMI shield), soldering, annealing and laser‐assisted bonding, to name just a few. In this article, we review several laser‐based processes used in advanced packaging and examine some of the key benefits and trade‐offs in order to help guide engineers to choosing the optimum source for their particular task.

Sustained-release liquisolid compact tablets containing artemether-lumefantrine as alternate-day regimen for malaria treatment to improve patient compliance.

The present study aimed to develop low-dose liquisolid tablets of two antimalarial drugs artemether–lumefantrine (AL) from a nanostructured lipid carrier (NLC) of lumefantrine (LUM) and estimate the potential of AL as an oral delivery system in malariogenic Wistar mice. LUM-NLCs were prepared by hot homogenization using Precirol® ATO 5/Transcutol® HP and tallow fat/Transcutol® HP optimized systems containing 3:1 ratios of the lipids, respectively, as the matrices. LUM-NLC characteristics, including morphology, particle size, zeta potential, encapsulation efficiency, yield, pH-dependent stability, and interaction studies, were investigated. Optimized LUM-NLCs were mixed with artemether powder and other dry ingredients and the resultant powder evaluated for micromeritics. Subsequent AL liquisolid tablets were tested for in vitro drug release and in vivo antiplasmodial activity in mice infected with Plasmodium berghei berghei (NK 65). Results showed that optimized LUM-NLC were stable, spherical, polydispersed but nanometric. Percentage yield and encapsulation efficiency were ~92% and 93% for Precirol® ATO 5/Transcutol® HP batch, then 81% and 95% for tallow fat/Transcutol® HP batch while LUM was amorphous in NLC matrix. In vitro AL release from liquisolid compacts revealed initial burst release and subsequent sustained release. Liquisolid tablet compacts formulated with Precirol® ATO 5/Transcutol® HP-AL4 achieved higher LUM release in simulated intestinal fluid (84.32%) than tallow fat/Transcutol® HP-BL3 (77.9%). Non-Fickian (anomalous) diffusion and super case II transport were the predominant mechanisms of drug release. Equal parasitemia reduction was observed for both batches of tablet compacts (~92%), superior to the reduction obtained with commercial antimalarial formulations: Coartem® tablets (86%) and chloroquine phosphate tablets (66%). No significant difference (P<0.05) in parasite reduction between double (4/24 mg/kg) and single (2/12 mg/kg) strength doses of AL compacts was observed. Our result highlights that AL could be formulated in much lower doses (4/24 mg/kg), for once-in-two days oral administration to improve patient compliance, which is currently not obtainable with conventional AL dosage forms.

Effect of ultrasonic melt treatment on the refinement of primary Al3Ti intermetallic in an Al–0.4Ti alloy

High intensity ultrasonic melt treatment was applied to an Al–0.4wt% Ti alloy over three selected temperature ranges: 810 to 770°C (above liquidus), 770 to 730°C (across liquidus), and 730 to 690°C (below liquidus). The size and morphology of the primary Al3Ti intermetallic particles were studied by scanning electron microscopy. It was found that the primary Al3Ti intermetallics were refined as a result of ultrasonication over all three temperature ranges and their morphology changed from typical large dendritic plates to small compact tablets. Quenching experiments before and after the ultrasonication were also carried out to capture the high-temperature stage of intermetallic formation. Based on the size and morphology observations, the mechanisms for the refinement of primary Al3Ti intermetallics at different solidification stages are discussed.

Usage of Molybdenum Nanocrystalline Powder for Radioisotope Production

Molybdenum nanocrystalline powder particles using electric blasting circuit method after molybdenum circuit destruction were formed. During this process the separate molybdenum-containing particles as products of the explosion reaction with each other and getting thinner during the cooling stage were combining. Their surface is partially oxygenated in argon (Ar) with air addition atmosphere. When cooling is finished the size distribution of the particles had three-modal profile, the most of the particles had 120nm diameter according to electronic microscope data. Oxygenated structures were not observed. Nanopowders were further mixed with sodium-chloride powder (in 5 and 10 mass % concentration) for further activation and pressing into dense tablets.These compact tablets in the nuclear reactor for the radioisotope production are supposed to be irradiated.

Effect of Particle Size on Detergent Powders Flowability and Tabletability

Detergent powders are sometimes processed into compact tablets for cleaning purposes based on the advantage of dosage, minimised dusting and packaging its offers over their powder counterpart. The flow-ability greatly influences handling. The particle size within the powder plays a key role on handling, flow-ability and the strength of the produced compact detergent tablet. The Ariel powder used in this study was separated into different size ranges via sieving; thereafter flowability, compression and compaction were carried out. The compressibility of the powder under 2 KN compaction force was analysed using Heckel equation. It was found that at the same compaction pressure, smaller size particle powders formed compact of greater tensile strength than larger particle. However, the powder with size range of 125-180 μm showed higher flowability compared to other size range.

Understanding the Tabletting Characteristics of Ficus deltoidea Powder by Fitting into Compression Models

AbstractThe objective of this paper was to investigate the characteristics of Ficus deltoidea powders during tablet formation using a direct compression method. To understand the data further, compression models were fitted, which included those of Heckel, Kawakita, Adams and Panelli–Filho. F. deltoidea is well‐known for its therapeutic properties when used in the form of an extracted powder. We further investigated the effect of the binders Avicel and Acdisol, which are known as a universal binder and a superdisintegrant, respectively. The physical properties, flowability and particle structures were determined to compare behavior and as references to the compression models used. The data were mostly consistent with those predicted by the compression models. As a result, applying compression models, especially the Kawakita model, was successfully performed and can be further related to the development and production of compact F. deltoidea tablets. Thus, this paper provides a fundamental understanding on the tabletting characteristics of F. deltoidea extract powder.Practical ApplicationsIn this study, a direct compression method was adopted to form the Ficus deltoidea extract powder into tablets. For further investigation, the F. deltoidea extract powder was mixed with two different binders, Avicel and Acdisol, in different ranges of composition. Hence, the pressure and effect of various process variables such as the food powder on tablet density and strength were obtained. For this reason, a study was conducted to increase our understanding of the tablet characteristics of F. deltoidea powder and binders by fitting the data into compression models. Four models had been proposed to reflect the physical and mechanical properties of powders and how these characteristics can be successfully applied in research. Finally, the best fitting compression model was chosen for further development and production of F. deltoidea compact tablets.

Assessing materials' tablet compaction properties using the Drucker–Prager Cap model

Compaction of powders into tablets is the most common method for producing solid dosage forms in the pharmaceutical industry. Despite the frequent use of compaction, the majority of commonly used methods for assessing compaction behavior of pharmaceutical materials are empirical in nature, and are not based on fundamental material properties. This can make it difficult to predict whether a material will fail to compact properly. This work describes the use of a physical model of the compaction process to determine relevant fundamental material properties, which will improve our ability to predict and control compaction problems. The parameters of the Drucker–Prager Cap (DPC) model of 14 materials, including excipients, active compounds and formulations are provided. The function of the DPC parameters with relative density is determined for each material. The material properties were compared at a common relative density of 0.85. Several of the formulations are known to have compaction risks, e.g. low tablet strength, high compaction force, or tablet defects. It is shown that insight into these materials' compaction behavior can be gained by examining these model parameters, as well as the stress distribution required to compact tablets. The development of this method will enable the evaluation of compaction risk using a small amount of material, and minimize the need for larger scale studies.

A possible application of magnetic resonance imaging for pharmaceutical research

Magnetic resonance imaging (MRI) is a non-destructive and non-invasive method, the experiment can be conducted in situ and allows the studying of the sample and the different processes in vitro or in vivo. 1D, 2D or 3D imaging can be undertaken. MRI is nowadays most widely used in medicine as a clinical diagnostic tool, but has still seen limited application in the food and pharmaceutical sciences. The different imaging pulse sequences of MRI allow to image the processes that take place in a wide scale range from ms (dissolution of compact tablets) to hours (hydration of drug delivery systems) for mobile as well as for rigid spins, usually protons. The paper gives examples of MRI application of in vitro imaging of pharmaceutical dosage based on hydroxypropyl methylcellulose which have focused on water-penetration, diffusion, polymer swelling, and drug release, characterized with respect to other physical parameters such as pH and the molecular weight of polymer. Tetracycline hydrochloride was used as a model drug. NMR imaging of density distributions and fast kinetics of the dissolution behavior of compact tablets is presented for paracetamol tablets.

Measurement and modelling of heat transfer in paper coating structures

Thermal conductivity of paper coatings is increasingly important in the performance of many printing processes, including traditional heatset web offset and thermal papers, as well as digital processes, such as electrophotography. This work studies the extension of a Modified Lumped Parameter Model, previously used successfully to describe talc coatings, to model the thermal conductivity–coating structure relationships of calcium carbonate (gcc: 60 wt% < 2 μm) coatings. A series of compact tablets were used to provide experimental values of thermal diffusivity and conductivity. The samples studied covered a range of latex binder addition levels, namely 0–25 parts, based on 100 parts pigment, of 0.2 μm styrene acrylate latex. Combining the observed thermal properties with knowledge of the pore structure changes induced by the latex addition, it is possible to establish initial correlation with the model, in which the connectivity of the structure is increased at low latex dose illustrating the initial increase in effective thermal conductivity. The practically hard sphere properties of the latex used, combined with the broad size distribution of the gcc, produce a disruptive packing effect as the dose level increases, such that the conductivity reflects a competition between the increasing connectivity provided by the latex versus the increasing relative pore size in the network structure. It is recognized that the fixed pigment volume in the model unit cell diverts from a true representation of the residual porosity. At the highest latex dose levels, the intrinsically less conducting properties of the latex begin to dominate.

Indirect, Reversible High-Density Hydrogen Storage in Compact Metal Ammine Salts

The indirect hydrogen storage capabilities of Mg(NH 3) 6Cl 2, Ca(NH 3) 8Cl 2, Mn(NH 3) 6Cl 2, and Ni(NH 3) 6Cl 2 are investigated. All four metal ammine chlorides can be compacted to solid tablets with densities of at least 95% of the crystal density. This gives very high indirect hydrogen densities both gravimetrically and volumetrically. Upon heating, NH 3 is released from the salts, and by employing an appropriate catalyst, H 2 can be released corresponding to up to 9.78 wt % H and 0.116 kg H/L for the Ca(NH 3) 8Cl 2 salt. The NH 3 release from all four salts is investigated using temperature-programmed desorption employing different heating rates. The desorption is found mainly to be limited by heat transfer, indicating that the desorption kinetics are extremely fast for all steps. During desorption from solid tablets of Mg(NH 3) 6Cl 2, Mn(NH 3) 6Cl 2, and Ni(NH 3) 6Cl 2, nanoporous structures develop, which facilitates desorption from the interior of large, compact tablets. Density functional theory calculations reproduce trends in desorption enthalpies for the systems studied, and a mechanism in which individual chains of the ammines are released from the surface of the crystal is proposed to explain the fast absorption/desorption processes.

Influence of some starch binders on the brittle fracture tendency of paracetamol tablets

The study was carried out to compare the binder effects of cassava and cocoyam starch with that of maize starch BP. The parameters investigated were the brittle fracture index (BFI), the tablet packing fraction (Pf), and tensile strength (T). Mucilages of the starches of varying concentrations; 15, 20, and 25% (w/v) were formed; their viscosities were determined and used to form paracetamol granules by wet-massing. The granules were compressed at different compression loads (arbitrary units on the load scale; 8, 9 and 9.5). At all given compression loads and at all binder concentration, cassava starch mucilages binder produced the hardest and most compact tablets with the least tendency to brittle fracture compared with cocoyam or maize starch mucilage. For instance, the BFI values at the compression load, 8 were 0.13 (tablets formed with cassava starch mucilage 20% w/v) 0.18 (tablets formed with cocoyam starch mucilage 20% w/v) and 0.35 (tablets formed with maize starch mucilage 20% w/v). Increase in compression load (8 to 9.5) increased the BFI of these tablets while an increase in binder concentration generally caused a decrease in BFI of these tablets. This decrease was less marked at higher compression load. The results indicate that cassava starch mucilage which was the most viscous, displayed the highest potential for ameliorating brittle fracture during manufacture of paracetamol tablets.

Influence of some starch binders on the brittle fracture tendency of paracetamol tablets

The study was carried out to compare the binder effects of cassava and cocoyam starch with that of maize starch BP. The parameters investigated were the brittle fracture index (BFI), the tablet packing fraction (Pf), and tensile strength (T). Mucilages of the starches of varying concentrations; 15, 20, and 25% (w/v) were formed; their viscosities were determined and used to form paracetamol granules by wet-massing. The granules were compressed at different compression loads (arbitrary units on the load scale; 8, 9 and 9.5). At all given compression loads and at all binder concentration, cassava starch mucilages binder produced the hardest and most compact tablets with the least tendency to brittle fracture compared with cocoyam or maize starch mucilage. For instance, the BFI values at the compression load, 8 were 0.13 (tablets formed with cassava starch mucilage 20% w/v) 0.18 (tablets formed with cocoyam starch mucilage 20% w/v) and 0.35 (tablets formed with maize starch mucilage 20% w/v). Increase in compression load (8 to 9.5) increased the BFI of these tablets while an increase in binder concentration generally caused a decrease in BFI of these tablets. This decrease was less marked at higher compression load. The results indicate that cassava starch mucilage which was the most viscous, displayed the highest potential for ameliorating brittle fracture during manufacture of paracetamol tablets. Key words: Cassava, cocoyam, maize starch, binder effect, tensile strength, brittle fracture index, tableting.

Discovery of Next Generation Inhibitors of HIV Protease

Due to factors such as resistance and long-term side effects as well as dosing regimen-related adherence issues, HIV therapy is a constantly moving target. HIV-1 protease inhibitors had an immediate and dramatic impact on the outcome of HIV/AIDS when launched in late 1995, and the search for new and improved next generation molecules has been under way in many laboratories. At GlaxoSmithKline (GSK) and Vertex Pharmaceuticals, this effort focused on two key issues, patient compliance and viral resistance. Using a water-solubilizing prodrug approach, the pill-burden in delivering our protease inhibitor, amprenavir, was dramatically decreased. By eliminating the large amounts of excipients necessary for the original soft-gel formulation, fosamprenavir (Lexiva/Telzir) delivers the clinically efficacious dose of amprenavir with two compact tablets per dose, compared to eight gel capsules. Our efforts to overcome viral resistance to 1(st) generation protease inhibitors by further elaborating the SAR of the amprenavir and related scaffolds, led to successive and dramatic improvements in wild-type antiviral potencies, and ultimately to the discovery of "ultra-potent" molecules with very favorable overall resistance profiles. The selection of GW640385 (brecanvir--USAN approved only) as a clinical candidate and its progression into current phase 2 dose ranging studies represents the culmination of our effort toward next generation protease inhibitors.