Formation Of Drug Crystals Research Articles

COMPUTATIONAL TOOLS ASSISTED FORMULATION OPTIMIZATION OF NEBIVOLOL HYDROCHLORIDE LOADED PLGA NANOPARTICLES BY 32 FACTORIAL DESIGNS

Objective: The aim of the present study was to formulate and optimize the PLGA polymeric nanoparticle of Nebivolol Hydrochloride for sustain release of drug Methods: The drug-excipients interaction was explored by molecular docking studies by in silico tools. The drug-loaded polymeric nanoparticles prepared by emulsion solvent evaporation method using 32 factorial design and characterized for particle size, zeta potential, and entrapment efficiency. Shape and surface morphology was analysed by SEM and TEM. In vitro drug release study was performed by using a diffusion membrane. Results: The docking analysis inferred that the drug has interacted well with PLGA and PF-68, which could prevent the drug crystal formation. The optimized polymeric nanoparticles had a particle size of 291 nm and entrapment efficiency of 83.4% and were found to be within 95% of CI of the predicted value, which is acceptable. SEM and TEM studies showed that the formed polymeric nanoparticles were smooth, spherical in shape and uniform in size. In vitro drug release study of optimized formulation showed sustained release for prolonged time period Conclusion: Based on the computational studies and in vitro release studies, the developed Nebivolol hydrochloride loaded in PLGA nanoparticles could be a promising formulation in oral drug delivery for the treatment of hypertension.

Coupling of Fused Deposition Modeling and Inkjet Printing to Produce Drug Loaded 3D Printed Tablets.

In the current study, we have coupled Fused Deposition Modelling (FDM) for the fabrication of plain polyvinyl alcohol (PVA) tablets followed by dispensing of minoxidil ethanolic solutions using inkjet printing. The use of a drop-on-solid printing approach facilitates an accurate and reproducible process while it controls the deposition of the drug amounts. For the purpose of the study, the effect of the solvent was investigated and minoxidil ink solutions of ethanol 70% v/v (P70) or absolute ethanol (P100) were applied on the plain PVA tablets. Physicochemical characterization showed that solvent miscibility with the polymer substrate plays a key role and can lead to the formation of drug crystals on the surface or drug absorption in the polymer matrix. The produced minoxidil tablets showed sustained release profiles or initial bursts strongly affected by the solvent grade used for dispensing the required dose on drug loaded 3D printed tablets. This paradigm demonstrates that the coupling of FDM and inkjet printing technologies could be used for rapid development of personalized dosage forms.

Optimized Encapsulation of the FLAP/PGES-1 Inhibitor BRP-187 in PVA-Stabilized PLGA Nanoparticles Using Microfluidics.

The dual inhibitor of the 5-lipoxygenase-activating protein (FLAP) and the microsomal prostaglandin E2 synthase-1 (mPGES-1), named BRP-187, represents a promising drug candidate due to its improved anti-inflammatory efficacy along with potentially reduced side effects in comparison to non-steroidal anti-inflammatory drugs (NSAIDs). However, BRP-187 is an acidic lipophilic drug and reveals only poor water solubility along with a strong tendency for plasma protein binding. Therefore, encapsulation in polymeric nanoparticles is a promising approach to enable its therapeutic use. With the aim to optimize the encapsulation of BRP-187 into poly(lactic-co-glycolic acid) (PLGA) nanoparticles, a single-phase herringbone microfluidic mixer was used for the particle preparation. Various formulation parameters, such as total flow rates, flow rate ratio, the concentration of the poly(vinyl alcohol) (PVA) as a surfactant, initial polymer concentration, as well as presence of a co-solvent on the final particle size distribution and drug loading, were screened for best particle characteristics and highest drug loading capacities. While the size of the particles remained in the targeted region between 121 and 259 nm with low polydispersities (0.05 to 0.2), large differences were found in the BRP-187 loading capacities (LC = 0.5 to 7.29%) and drug crystal formation during the various formulations.

Electrospun Transdermal Patch for Contraceptive Hormone Delivery.

A transdermal patch for delivery of Levonorgestrel (LNG) can be used for long-acting contraception. In this study, we designed and characterized a patch made of nonwoven electrospun microfibers comprised of Polycaprolactone (PCL) encapsulating LNG for slow release in a mineral oil matrix. Scanning electron microscopy showed uniform, randomly oriented PCL fibers with large interconnected voids filled with mineral oil. Thermogravimetric analysis indicated that LNG loaded into PCL fibers had thermal stability up to ~200°C. Differential Scanning Calorimetry suggested that LNG was dispersed in the electrospun fibers without interaction between the LNG and PCL, and without formation of drug crystals. Fourier Transform Infrared spectroscopy and X-ray diffraction results further supported the conclusion that there was no chemical drug-polymer interaction in LNGloaded fibers. Effective in vitro flux (i) from patches into mineral oil was 1.9 µgcm-2h-1, (ii) from mineral oil across porcine skin was 4.6 µgcm-2h-1 and (iii) from patches across porcine skin was 1.7 μgcm- 2h-1, indicating that transdermal delivery rate was controlled by a combination of the patch and the skin. The LNG-loaded patches demonstrated steady delivery of LNG across skin for up to 5 days in vitro. With additional development, LNG-loaded electrospun PCL patches could be used for long-acting contraception.

Polymer degradation induced drug precipitation in PLGA implants – Why less is sometimes more

Nifedipine and nicardipine loaded PLGA extrudates have a great potential to prevent cerebral vasospasms after subarachnoid hemorrhage or surgical clipping of aneurysm. A constant release over approx. two weeks is desired. Although in vivo studies on humans have been reported, there is limited knowledge about the release kinetics and the underlying mechanisms. Therefore, nifedipine and nicardipine loaded PLGA implants with different drug loads were manufactured by extrusion and investigated. In addition to the measurements of the release kinetics, GPC, DSC, X-ray diffraction and light microscopic investigations were performed for a detailed characterization. The water uptake and polymer erosion studies showed an initial lag phase of 5–7 days and an acceleration of both processes thereafter. With 5% loaded implants a higher drug release compared to 10% drug loaded polymers could be achieved and not only the relative amount of drug release (% of loaded drug), but surprisingly also the absolute amount of the released drug increased. The drugs were initially in an amorphous state. For nifedipine, formation of drug crystals with time has been observed by light microscopy and X-ray diffraction. The analysis of the drug content in the degrading polymer showed a very large increase from 10% to about 20% (nifedipine) and over 50% (nicardipine). In contrast, no or only a moderate increase of the drug content occurred for initially 5% loaded polymer implants. We postulate that water penetration and polymer degradation induced changes of the microenvironment lead to supersaturated systems. A supersaturated state is faster reached for polymers with higher drug load and therefore, drug precipitation takes place at earlier time points.As a result, drug release might be incomplete for poorly soluble drugs and paradoxically, the total amount of drug release might be higher for systems with a lower drug load. Drug release is initially controlled by the PLGA matrix, but later by the dissolution kinetics of the precipitated drug which are very slow for poorly soluble drugs according to the Noyes-Whitney equation.

Tri-block polymer with interfacial layer formation ability and its use in maintaining supersaturated drug solution after dissolution of solid dispersions

BackgroundMaintaining a supersaturated drug solution after the dissolution of the solid dispersions of water insoluble drugs continues to be a great challenge and is important to the oral bioavailability enhancement of hardly soluble drugs.MethodsNimodipine solid dispersions were prepared by hot-melt extrusion and a special tri-block polymer was employed as a co-carrier. The solid dispersions were characterized by modulated differential scanning calorimetry, transmission electron microscopy, hydrogen-nuclear magnetic resonance and so on.ResultsThe tri-block polymer was able to inhibit the formation of drug crystals after dissolution of the solid dispersions. Due to the unique interfacial layer formation ability of the tri-block polymer, a special drug loading micelle which encapsulated the compound and the hydrophobic fragments of the copolymers appeared in the release media. The tri-block polymer was composed of a hydrophilic part forming the shell of micelles, a hydrophobic part shaping the core of micelles, and a special intermediate hydrophilicity part constructing the interfacial layer of micelles.ConclusionThe tri-block polymer was not only able to stabilize the supersaturated drug solution of solid dispersions to enhance the oral bioavailability of hardly soluble drugs, but is also a potential candidate to construct micelles for systemic administration, due to the good compatibility and organic solvents free micelle formation procedure.

Micro-structured 3D-electrospun scaffolds of biodegradable block copolymers for soft tissue regeneration

The present article describes the application of a poly(ethylene terephthalate) mesh as template for the preparation of micro-structured fibres mat by electrospinning of biodegradable triblock copolymers based on polylactic acid and poly(butylene succinate/azelate) random copolymer. These copolymers present and excellent controlled biodegradation process in physiological conditions, with interesting applications in targeting and controlled release of different drugs.After the application of the poly(ethylene terephthalate) mesh in the electrospinning process, the detachment of the template provides a specific oriented microfibres mat, that affect to the adhesion and proliferation of cell seeded on the networks. In addition, the microfibres mats were loaded with dexamethasone as anti-inflammatory drug. The release of the drug takes place in a controlled relative short period due to the formation of drug crystals on the surface of the fibres during the electrospinning process. This issue can be restrained by acting on the triblock copolymer composition, improving the drug-polymer compatibility. Copolymerization also allows the modulation of the biodegradation rate. The biodegradable scaffolds under investigation can be therefore considered very promising for regenerative medicine and soft tissue engineering.

Tamoxifen citrate-loaded poly(d,l) lactic acid nanoparticles: Evaluation for their anticancer activity in vitro and in vivo

The optimization of tamoxifen citrate entrapment and its release from biodegradable poly(d,l) lactic acid nanoparticles are prepared by modified spontaneous emulsification solvent diffusion method. Since the addition of tamoxifen citrate induces the formation of drug crystals from nanoparticle suspension the influence of several parameters on tamoxifen citrate encapsulation was investigated. In vitro studies for cytotoxicity, DNA ladder, and the expression of Bcl-2-Bax expression were also investigated for MCF-7 and MDA-MB-231 cells after the addition of tamoxifen citrate alone and tamoxifen citrate-poly(d,l) lactic acid-nanoparticles (encapsulated tamoxifen citrate). From results, it was noticed that the size and zeta potential of the drug loaded nanoparticles were not differed much in their physicochemical properties from drug free counterparts. The drug-loaded and drug-free nanoparticles exhibited size of in between 271.4 and 282.7 nm and zeta potential of -34 to -27.4 mV, respectively. There was significant increase in drug incorporation in the particles noticed in dichloromethane + methanol system in comparison to acetone + methanol and ethyl acetate + methanol systems. The drug was partly released from the nanoparticles after 48 h of incubation at 37℃. From Fourier transform infrared spectroscopy and differential scanning calorimetry data demonstrated drug-polymer characteristics within the nanoparticles and unincorporated drug that appeared in the form of crystals from polarized microscopic study. MCF-7 and MDA-MB-231 cells were more sensitive to tamoxifen citrate-poly(d,l) lactic acid-nanoparticles than tamoxifen citrate alone. DNA ladder and the expression of Bax to Bcl-2 ratio were much higher in tamoxifen citrate encapsulated in nanoparticles than that in tamoxifen citrate alone. These results demonstrated the feasibility of encapsulation of tamoxifen citrate and its enhanced efficiency in vitro and in vivo studies.

Drug permeation and cellular interaction of amino acid-coated drug combination powders for pulmonary delivery

The effect of three amino acid coatings (l-leucine, l-valine and l-phenylalanine) on particle integrity, aerosolization properties, cellular interaction, cytocompatibility, and drug permeation properties of drug combination powder particles (beclomethasone dipropionate and salbutamol sulphate) for dry powder inhalation (DPI) was investigated. Particles with crystalline l-leucine coating resulted in intact separated particles, with crystalline l-valine coating in slightly sintered particles and with amorphous l-phenylalanine coating in strongly fused particles. The permeation of beclomethasone dipropionate across a Calu-3 differentiated cell monolayer was increased when compared with its physical mixture. Drug crystal formation was also observed on the Calu-3 cell monolayer. The l-leucine coated particles were further investigated for cytocompatibility in three human pulmonary (Calu-3, A549 and BEAS-2B) and one human macrophage (THP-1) cell lines, where they showed excellent tolerability. The l-leucine coated particles were also examined for their ability to elicit reactive oxygen species in pulmonary BEAS-2B and macrophage THP-1 cell lines. The study showed the influence of the amino acid coatings for particle formation and performance and their feasibility for combination therapy for pulmonary delivery.

Preparation of a novel starch-derived three-dimensional ordered macroporous carbon for improving the dissolution rate and oral bioavailability of water-insoluble drugs

In our study, soluble starch was applied as a novel carbon source for preparing three-dimensional ordered macroporous carbon (3DOMC) using monodisperse silica nanospheres as the hard template. The 3DOMC was used as an insoluble drug carrier when it was found that it could markedly improve the water solubility of felodipine (FDP). The structural features of 3DOMC were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The 3DOMC structure was found to have a higher drug loading than microporous and mesoporous structures, and the interconnected nanostructure effectively inhibited the formation of drug crystals. FDP, belonging to the Biopharmaceutics Classification System II (BCSII), was chosen as the model drug and was loaded into the 3DOMC structure by solvent evaporation. The state of FDP in the 3DOMC structure was characterized by powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). The results obtained showed that FDP was present in the pores in an amorphous or microcrystalline state. In vivo and in vitro experiments indicated that 3DOMC could significantly improve the drug dissolution rate, but the FDP-3DOMC self-made common tablets had the disadvantage of a burst effect. For this reason, osmotic pump technology was used to control the drug release rate. We developed a potentially useful insoluble drug carrier for pharmaceutical applications.

Studies on Aspirin Crystals Generated by a Modified Vapor Diffusion Method.

The objectives of the current investigation were (1) to study the influence of selected two different non-solvents (diethylether and dichloromethane) on the drug crystal formation of a model drug, aspirin (ASP-I) by the modified vapor diffusion method and (2) to characterize and compare the generated crystals (ASP-II and ASP-III) using different analytical techniques with that of unprocessed ASP-I. When compared to the classical vapor diffusion method which consumes about 15days to generate drug crystals, the modified method needs only 12h to get the same. Fourier transform-infrared spectroscopy (FT-IR) reveals that the internal structures of ASP-II and ASP-III crystals were identical when compared with ASP-I. Although the drug crystals showed a close similarity in X-ray diffraction patterns, the difference in the relative intensities of some of the diffraction peaks (especially at 2θ values of around 7.7 and 15.5) could be attributed to the crystal habit or crystal size modification. Similarly, the differential scanning calorimetry (DSC) study speculates that only the crystal habit modifications might occur but without involving any change in internal structure of the generated drug polymorphic form I. This is further substantiated from the scanning electron microscopy (SEM) pictures that indicated the formation of platy shape for the ASP-II crystals and needle shape for the ASP-III crystals. In addition, the observed slow dissolution of ASP crystals should indicate polymorph form I formation. Thus, the modified vapor diffusion method could routinely be used to screen and legally secure all possible forms of other drug entities too.

Transdermal delivery of Diltiazem HCl from matrix film: Effect of penetration enhancers and study of antihypertensive activity in rabbit model

The present investigation focused on the development of Diltiazem HCl (DTH) matrix film and its characterization by in-vitro, ex-vivo and in-vivo methods. Films were prepared by solvent casting method by taking different ratios of hydroxypropyl methylcellulose K4M (HPMC K4M) and Eudragit RS100. Various parameters of the films were analyzed such as mechanical property using tensile tester, interaction study by Fourier transform infrared spectroscopy (FTIR) and Thermogravimetric analysis (TGA), in-vitro drug release through cellulose acetate membrane, ex-vivo permeation study using abdominal skin of rat employing Franz diffusion cell, and in-vivo antihypertensive activity using rabbit model. The FTIR studies confirmed the absence of interaction between DTH and selected polymers. Thermal analysis showed the shifting of endothermic peak of DTH in film, indicating the dispersion of DTH in molecular form throughout the film. Incorporation of 1,8-cineole showed highest flux (89.7μg/cm2/h) of DTH compared to other penetration enhancers such as capsaicin, dimethyl sulfoxide (DMSO), and N-methyl pyrrolidone (NMP). Photomicrographs of histology study on optimized formulation (DF9) illustrated disruption of stratum corneum (SC) supporting the ex-vivo results. The in-vivo antihypertensive activity results demonstrated that formulation DF9 was effective in reducing arterial blood pressure in normotensive rabbits. SEM analysis of films kept for stability study (40±2°C/75%±5%RH for 3months) revealed the formation of drug crystals which may be due to higher temperature. The findings of the study provide a better alternative dosage form of DTH for the effective treatment of hypertension with enhanced patient compliance.

Equilibrium state at supersaturated drug concentration achieved by hydroxypropyl methylcellulose acetate succinate: molecular characterization using (1)H NMR technique.

The maintenance mechanism of the supersaturated state of poorly water-soluble drugs, glibenclamide (GLB) and chlorthalidone (CLT), in hydroxypropyl methylcellulose acetate succinate (HPMC-AS) solution was investigated at a molecular level. HPMC-AS suppressed drug crystallization from supersaturated drug solution and maintained high supersaturated level of drugs with small amount of HPMC-AS for 24 h. However, the dissolution of crystalline GLB into HPMC-AS solution failed to produce supersaturated concentrations, although supersaturated concentrations were achieved by adding amorphous GLB to HPMC-AS solution. HPMC-AS did not improve drug dissolution and/or solubility but efficiently inhibited drug crystallization from supersaturated drug solutions. Such an inhibiting effect led to the long-term maintenance of the amorphous state of GLB in HPMC-AS solution. NMR measurements showed that HPMC-AS suppressed the molecular mobility of CLT depending on their supersaturation level. Highly supersaturated CLT in HPMC-AS solution formed a gel-like structure with HPMC-AS in which the molecular mobility of the CLT was strongly suppressed. The gel-like structure of HPMC-AS could inhibit the reorganization from drug prenuclear aggregates to the crystal nuclei and delay the formation of drug crystals. The prolongation subsequently led to the redissolution of the aggregated drugs in aqueous solution and formed the equilibrium state at the supersaturated drug concentration in HPMC-AS solution. The equilibrium state formation of supersaturated drugs by HPMC-AS should be an essential mechanism underlying the marked drug concentration improvement.

Overcoming drug crystallization in electrospun fibers – Elucidating key parameters and developing strategies for drug delivery

For the development of novel therapeutics, uncontrolled crystallization of drugs within delivery systems represents a major challenge. Especially for thin and flexible polymeric systems such as oral films or dermal wound dressings, the formation and growth of drug crystals can significantly affect drug distribution and release kinetics as well as physical storage stability. In this context, electrospinning was introduced as a fabrication technique with the potential to encapsulate drugs within ultrafine fibers by rapid solvent evaporation overcoming drug crystallization during fabrication and storage. However, these effects could so far only be shown for specific drug-polymer combinations and an in-depth understanding of the underlying processes of drug-loaded fiber formation and influencing key parameters is still missing.In this study, we systematically investigated crystal formation of caffeine as a model drug in electrospun fibers comparing different polymers. The solvent polarity was found to have a major impact on the drug crystal formation, whereas only a minor effect was attributed to the electrospinning process parameters.Based on an in-depth understanding of the underlying processes determining drug crystallization processes in electrospun fibers, key parameters could be identified which allow for the rational development of drug-loaded electrospun fibers overcoming drug crystallization.

Internal Structure and Size Matters of Polyester Nanoparticles Encapsulating a Bioactive Hydrophobic Drug for the Prevention of Drug Crystals in Aqueous Systems

This study presents a way of preventing a highly hydrophobic bioactive drug encapsulated in polycaprolactone (PCL) nanoparticles from forming drug crystals aqueous systems. Thymol trimethoxycinnamate was selected as a hydrophobic bioactive model drug. Four PCL-drug nanoparticles were prepared: their internal structures and sizes were regulated by introducing different types of PCL or by changing polymer compositions during the preparation of the nanoparticles. The formation of drug crystals from the PCL-drug nanoparticles was observed by optical microscopy at two temperatures (25 and 40 °C) and in three aqueous mediums (deionized water or aqueous solutions containing 5 wt % butylene glycol or ethanol). In deionized water, the formation of drug crystals could be prevented if PCL-drug nanoparticles have highly crystalline cores. In aqueous solutions containing butylene glycol or ethanol, both the internal crystalline core and the size of the nanoparticles could be important in preventing the drug crystal formation. The present study provides both scientific and practical information to those who involve the drug delivery system and pharmaceutical sciences where drugs are engineered to increase the therapeutic efficiency through polymeric nanoparticles.

Encapsulation of dexamethasone into biodegradable polymeric nanoparticles

The present paper concerns both the optimization of dexamethasone (DXM) entrapment and its release from biodegradable poly( d, l-lactide- co-glycolide) (PLGA) nanoparticles prepared by the solvent evaporation process. Since the addition of DXM induced the formation of drug crystals beside the nanoparticle suspension, the influence of several parameters on DXM encapsulation was investigated such as the type of organic solvent and polymer, the DXM initial mass, the evaporation rate of the solvent, the continuous phase saturation and the incorporation of a lipid in the polymer. Nanoparticle size and zeta potential were not modified in the presence of DXM and were respectively around 230 nm and −4 mV. The highest drug loading was obtained using 100 mg PLGA 75:25 in a mixture of acetone-dichloromethane 1:1 (v:v) and 10 mg of DXM. The drug was completely released from this optimized formulation after 4 h of incubation at 37 °C. Neither the evaporation rate of the organic solvent, nor the aqueous phase saturation with salt or the incorporation of 1 mg 1,2-dipalmitoyl- sn-glycero-3-phosphocholine (DPPC) within the nanoparticles modified the encapsulation efficiency. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) demonstrated that the drug was molecularly dispersed within the nanoparticles whereas the non-encapsulated DXM crystallized. These results demonstrate the feasibility of encapsulating dexamethasone and its subsequent delivery.

Design and Evaluation of an Emulsion Vehicle for Paclitaxel. I. Physicochemical Properties and Plasma Stability

The current formulation of paclitaxel contains ethanol and Cremophor EL and has been reported to cause serious adverse reactions. The purpose of the present work was to develop an improved emulsion vehicle for paclitaxel and to study the physicochemical properties of such a system. Emulsions were prepared by either microfluidization or sonication method and the droplet size characterized by dynamic light scattering and light microscopy. Stable emulsions could be made using mixtures of lecithin/sodium deoxycholate as the emulsifiers. The formulation was further improved by using a combination of free acid and the sodium salt. Paclitaxel could be loaded into the emulsions at 2.5 mg/ml without the formation of drug crystals. While these emulsions were stable on storage, they flocculated when mixed with plasma. Steric stabilization of the emulsion droplets with poloxamer 188 increased the stability of the emulsions in plasma but promoted the crystallization of paclitaxel. The crystallization tendency could be reduced by using PEG5000PE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[poly (ethylene glycol) 5000]), a less water-soluble stabilizer. Emulsions with good stability characteristics containing 2.5 mg/ml paclitaxel could be made using bile salt/acid and lecithin, and the excellent stability of these emulsions in plasma was achieved by steric stabilization using PEG5000PE.

Eudragits: Role as crystallization inhibitors in drug-in-adhesive transdermal systems of estradiol

A transdermal steroidal delivery system usually contains a high concentration of drug to obtain high drug fluxes. The present investigation involved the development of drug-in-adhesive transdermal systems of estradiol using synthesized acrylate copolymer (EA) of 2-ethylhexyl acrylate and acrylic acid. The effect of several variables such as varying drug polymer ratios, effect of Eudragit ® RL PO and Eudragit ® E PO and effect of drying temperatures on prevention of drug crystallization in the formulation matrix was investigated. The systems free from drug crystals were evaluated and compared with a marketed formulation with respect to its skin permeation profile. The optimized formulation was also subjected to accelerated stability testing. Eudragit ® RL PO and Eudragit ® E PO were found to be effective as crystallization inhibitors in the transdermal matrix systems tested. Formulations fabricated with Eudragit ® E PO gave transparent systems with good film properties and a higher skin permeation profile as compared to that of the marketed system. Higher temperature and humidity conditions facilitated the formation of drug crystals, whereas no crystals were observed in the formulation matrix at 23±0.5°C and at 30±1°C for the period of 6 months studied.

Rapidly Progressive Acute Renal Failure Due to Acyclovir: Case Report and Review of the Literature

Acyclovir nephrotoxicity has been described since the inception of the drug's use more than a decade ago. Acute renal failure mediated by this compound is characterized by abrupt elevations in serum creatinine and a gradual return to baseline renal function on discontinuation of the drug. Drug crystal formation in collecting tubules resulting in an intraparenchymal form of obstructive nephropathy has been suggested as the mechanism for acyclovir nephrotoxicity. The patient we present developed rapidly progressive acute renal failure with concomitant mental status changes in the setting of treatment with high-dose parenteral acyclovir. Acyclovir therapy was discontinued and an open renal biopsy was obtained to further evaluate our patient's diminishing renal function. Pathologic examination of the biopsy specimen revealed loss of proximal tubule brush border and dilated proximal and distal tubules with flattening of lining cells and focal nuclear loss. No crystals were noted. These changes were consistent with acute tubular necrosis with regeneration. Over the next 4 days our patient's renal and neurologic levels recovered to their prehospitalization statuses. It appears that our patient was affected by acyclovir-mediated nephrotoxicity that manifested on biopsy by acute tubular necrosis and the absence of crystalluria or crystal deposition. Intravenous acyclovir treatment can therefore produce rapidly progressive acute neurologic and renal toxicity that is usually reversible. The pathologic changes of acute tubular necrosis must now be included as part of the spectrum of renal damage associated with acyclovir therapy.