Sub-50 nm ultra-small organic drug nanosuspension prepared by cavi-precipitation and its brain targeting potential.

The purpose of this study was to show whether it is possible to prepare sub 100 nm or preferably sub-50 nm drug nanosuspension (NS) of suitable quality for intravenous administration. Furthermore, we have studied how the brain targeting potential of such small size organic NS differs from relatively bigger size NS. Two combination technologies (cavi-precipitation, H96) and a standard high-pressure homogenization (HPH) technology were used to prepare drug NS of different sizes. The cavi-precipitation process generated the smallest AmB NS, i.e., 27 nm compared to 79 nm by H96 technology and 252 nm by standard HPH technology. Dialysis of the nanosuspension in the original dispersion media was found to be the most efficient solvent removal method without negatively affecting particle size. The removal of organic solvent was found to drastically improve the stability of the formulations. The protein adsorption pattern shows that the small size NS particles obtained by the cavi-precipitation process have the potential to circulate longer in the bloodstream and have the potential to be taken up by the blood-brain barrier. The cavi-precipitation process generated ultrafine NS particles, which fulfilled the quality requirements for intravenous administration and offer a potential solution for brain targeting.

Can the cavi-precipitation process be exploited to generate smaller size drug nanocrystal?

OBJECTIVE: Cavi-precipitation has the potential to generate drug nanocrystals very efficiently. Achieving smaller than 100 nm particle size for organic drug substances still remained a challenge. The objective of this study was to demonstrate if cavi-precipitation technology can be used to generate smaller than 100 nm drug nanocrystal particle. SIGNIFICANCE: This study demonstrates that cavi-precipitation process can be used to generate drug nanocrystals of the model compound resveratrol (RVT) consists of crystallites of 30-50 nm size. METHOD: RVT was dissolved in different organic solvents to prepare the solvent phase (S-phase). Several stabilizers were tested for the organic phase. A combination of SDS and PVP was used stabilizer system in the aqueous anti-solvent phase (AS-phase). The S-phase was added to the AS-phase inside the Emulsiflex C5 homogenizer. Nanosuspension was characterized by laser diffractometry (LD), photon correlation spectroscopy (PCS) and scanning electron microscopy (SEM). The solid state of the suspended particles was investigated by powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC). RESULTS: It was found that DMSO, alone or in combination with acetone in the S-Phase generated the smallest size RVT nanocrystals. The optimum solvent (S) antisolvent (AS) ratio (S:AS) was found to be 3.6:56.4 (v:v). Span 20 was identified as the best stabilizer for the organic phase at a ratio (w:w) of 1:3 (Span 20:RVT). The particles precipitated from different solvents were predominantly crystalline. CONCLUSIONS: The best sample had a mean particle size (LD) of 167 nm [d(0.5)] which was composed of smaller crystallites having 30-50 nm size (SEM).

Advanced modification of drug nanocrystals by using novel fabrication and downstream approaches for tailor-made drug delivery.

Drug nanosuspensions/nanocrystals have been recognized as one useful and successful approach for drug delivery. Drug nanocrystals could be further decorated to possess extended functions (such as controlled release) and designed for special in vivo applications (such as drug tracking), which make best use of the advantages of drug nanocrystals. A lot of novel and advanced size reduction methods have been invented recently for special drug deliveries. In addition, some novel downstream processes have been combined with nanosuspensions, which have highly broadened its application areas (such as targeting) besides traditional routes. A large number of recent research publication regarding as nanocrystals focuses on above mentioned aspects, which have widely attracted attention. This review will focus on the recent development of nanocrystals and give an overview of regarding modification of nanocrystal by some new approaches for tailor-made drug delivery.

The Scalability of Wet Ball Milling for The Production of Nanosuspensions.

BACKGROUND: Miniaturization of nanosuspensions preparation is a necessity in order to enable proper formulation screening before nanosizing can be performed on a large scale. Ideally, the information generated at small scale is predictive for large scale production. OBJECTIVE: This study was aimed to investigate the scalability when producing nanosuspensions starting from a 10 g scale of nanosuspension using low energy wet ball milling up to production scales of 120 g nanosuspension and 2 kg nanosuspension by using a standard high energy wet ball milling operated in batch mode or recirculation mode, respectively. METHODS: Two different active pharmaceutical ingredients, i.e. curcumin and hesperetin, have been used in this study. The investigated factors include the milling time, milling speed, and the type of mill. RESULTS: Comparable particle sizes of about 151 nm to 190 nm were obtained for both active pharmaceutical ingredients at the same milling time and milling speed when the drugs were processed at 10 g using low energy wet ball milling or 120 g using high energy wet ball milling in batch mode, respectively. However, an adjustment of the milling speed was needed for the 2 kg scale produced using high energy wet ball milling in recirculation mode to obtain particle sizes comparable to the small scale process. CONCLUSION: These results confirm in general, the scalability of wet ball milling as well as the suitability of small scale processing in order to correctly identify the most suitable formulations for large scale production using high energy milling.

Production of drug nanosuspensions: effect of drug physical properties on nanosizing efficiency.

OBJECTIVE: Drug nanosuspension is one of the established methods to improve the bioavailability of poorly soluble drugs. Drug physical properties aspect (morphology, solid state, starting size et al) is a critical parameter determining the production efficiency. Some drug modification approaches such as spray-drying were proved to improve the millability of drug powders. However, the mechanism behind those improved performances is unclear. This study is to systematically investigate the influence of those physical properties. METHODS: Five different APIs (active pharmaceutical ingredients) with different millabilities, i.e. resveratrol, hesperetin, glibenclamide, rutin, and quercetin, were processed by standard high pressure homogenization (HPH), wet bead milling (WBM), and a combinative method of spray-drying and HPH. RESULTS: Smaller starting sizes of certain APIs could accelerate the particle size reduction velocity during both HPH and WBM processes. Spherical particles were observed for almost all spray-dried powders (except spray-dried hesperetin) after spray-drying. The crystallinity of some spray-dried samples such as rutin and glibenclamide became much lower than their corresponding unmodified powders. Almost all spray-dried drug powders after HPH processes could lead to smaller nanocrystal particle size than unmodified APIs. CONCLUSION: The modified microstructure instead of solid state after spray-drying explained the potential reason for improved nanosizing efficiency. In addition, the contribution of starting size on the production efficiency was also critical according to both HPH and WBM results.

Systematical Investigation of Different Drug Nanocrystal Technologies to Produce Fast Dissolving Meloxicam Tablets.

Three different methods, i.e., high-pressure homogenization, wet bead milling, and a combination approach of freeze-drying and high-pressure homogenization, were used to produce meloxicam nanosuspensions, respectively. Wet bead milling led to the nanosuspensions with smallest particle size (88 nm) after 4 h and optimal dissolution performances. Freeze-dried meloxicam powder could highly improve the size reduction efficiency compared to the unmodified drug and particle size of the freeze-dried sample could be reduced to 342 nm after only one homogenization cycle at 1000 bar. The polymorphism transition and change of the particle morphology after the lyophilization might be important reasons to affect the nanosizing processes. Interestingly, the tablets prepared by using nanosuspensions from homogenizer and combination process showed faster dissolution in the first 20 min than the bead milling nanocrystal tablets.

Systematical investigation of a combinative particle size reduction technology for production of resveratrol nanosuspensions.

Nanosizing is frequently used as formulation approach to increase the bioavailability of poorly water-soluble drugs. However, standard size reduction processes can be relatively time-consuming. It was found that the modification of the physical properties of a starting material by means of spray-drying can be used to improve the effectiveness of a subsequently performed high pressure homogenization. Such a process belongs to the combinative particle size reduction methods and is also referred to as H 42 process. Based on previous studies, it was hypothesized that the improved efficiency was a result of reduced crystallinity of the modified drug. The present study was conducted in order to asses this hypothesis in a systematical manner by applying design of experiment (DoE) principles. Resveratrol was selected as model compound for this study. It was processed by both standard high pressure homogenization and by a combinative particle size reduction process (the H42 process). An optimized resveratrol/surfactant ratio for the spray-dried intermediate was identified by using the response-surface methodology. The optimization led to a nanosuspension with a mean particle size of 192 nm, which is much smaller than the mean particle size of 569 nm when standard high pressure homogenization was used. Both predominately crystalline and predominately amorphous solids resulted from the spray-drying process. In contrast to the initial hypothesis, the smallest particle sizes were achieved by processing predominately crystalline intermediate with high pressure homogenization.

Effect of drug physico-chemical properties on the efficiency of top-down process and characterization of nanosuspension.

INTRODUCTION: The top-down approach is frequently used for drug nanocrystal production. A large number of review papers have referred to the top-down approach in terms of process parameters such as stabilizer selection. However, a very important factor, that is, the influence of drug properties, has been not addressed so far. AREAS COVERED: This review will first discuss different nanocrystal technologies in brief. The focus will be on reviewing the different drug properties such as solid state and particle morphology on the efficiency of particle size reduction during top-down processes. Furthermore, the drug properties in the final nanosuspensions are critical for drug dissolution velocity. Therefore, another focus is the characterization of drugs in obtained nanosuspension. EXPERT OPINION: Drug physical properties play an important role in the production efficiency. The combinative technologies using modified drugs could significantly improve the performances of top-down processes. However, further understanding of the drug millability and homogenization will still be needed. In addition, a carefully established characterization system for nansuspension is essential.

Systematic screening of different surface modifiers for the production of physically stable nanosuspensions.

The role of a surface modifier is important in the formation of stable nanosuspensions. In this study, a simple and systematic screening method for selecting optimum surface modifiers was performed by utilizing a low-energy wet ball milling method. Nine surface modifiers from different classes with different stabilization mechanisms were applied on six different models of active pharmaceutical ingredients (API). Particle size analysis showed that at concentration five times higher than the critical micelle concentration, SDS and sodium cholate (anionic surfactant) showed the highest percent success to produce stable nanosuspensions with particle size smaller than 250 nm. Similar findings were also shown by poloxamer 188 (nonionic surfactant) and hydroxypropylmethylcellulose E5 (polymeric stabilizer) at concentration 1% (w/v) and 0.8% (w/v), respectively. In addition, combinations of anionic surfactant and nonionic surfactant as well as combinations of anionic surfactant and polymeric stabilizer showed high percent success in the formation of stable nanosuspensions. In general, no correlation can be found between the physicochemical characteristics of the model API (molecular weight, melting point, log P, pKa, and crystallinity) with its feasibility to be nanosized. The concentration and the principle of stabilization of surface modifier determine the formation of stable nanosuspensions.

Systematic Screening of Different Surface Modifiers for the Production of Physically Stable Nanosuspensions.

The role of a surface modifier is important in the formation of stable nanosuspensions. In this study, a simple and systematic screening method for selecting optimum surface modifiers was performed by utilizing a low-energy wet ball milling method. Nine surface modifiers from different classes with different stabilization mechanisms were applied on six different models of active pharmaceutical ingredients (API). Particle size analysis showed that at concentration five times higher than the critical micelle concentration, SDS and sodium cholate (anionic surfactant) showed the highest percent success to produce stable nanosuspensions with particle size smaller than 250nm. Similar findings were also shown by poloxamer 188 (nonionic surfactant) and hydroxypropylmethylcellulose E5 (polymeric stabilizer) at concentration 1% (w/v) and 0.8% (w/v), respectively. In addition, combinations of anionic surfactant and nonionic surfactant as well as combinations of anionic surfactant and polymeric stabilizer showed high percent success in the formation of stable nanosuspensions. In general, no correlation can be found between the physicochemical characteristics of the model API (molecular weight, melting point, log P, pKa, and crystallinity) with its feasibility to be nanosized. The concentration and the principle of stabilization of surface modifier determine the formation of stable nanosuspensions. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Combinative Particle Size Reduction Technologies for the Production of Drug Nanocrystals.

Nanosizing is a suitable method to enhance the dissolution rate and therefore the bioavailability of poorly soluble drugs. The success of the particle size reduction processes depends on critical factors such as the employed technology, equipment, and drug physicochemical properties. High pressure homogenization and wet bead milling are standard comminution techniques that have been already employed to successfully formulate poorly soluble drugs and bring them to market. However, these techniques have limitations in their particle size reduction performance, such as long production times and the necessity of employing a micronized drug as the starting material. This review article discusses the development of combinative methods, such as the NANOEDGE, H 96, H 69, H 42, and CT technologies. These processes were developed to improve the particle size reduction effectiveness of the standard techniques. These novel technologies can combine bottom-up and/or top-down techniques in a two-step process. The combinative processes lead in general to improved particle size reduction effectiveness. Faster production of drug nanocrystals and smaller final mean particle sizes are among the main advantages. The combinative particle size reduction technologies are very useful formulation tools, and they will continue acquiring importance for the production of drug nanocrystals.

Systematic investigation of the cavi-precipitation process for the production of ibuprofen nanocrystals.

Cavi-precipitation process is a combinative particle size reduction technology based on solvent-anti-solvent precipitation coupled high pressure homogenization (HPH). The cavi-precipitation can be used for the efficient production of drug nanocrystals (NC) with improved dissolution rate leading to better bioavailability. The work presented here demonstrates the advantage of cavi-precipitation process over the standard HPH processes and standard combination process (decoupled process) where precipitation is performed outside the homogenizer. The model compound ibuprofen (IBP) was solubilized in isopropanol (IPA) to constitute the solvent phase and mixed with the anti-solvent phase (0.1% (w/v) hydroxypropyl methylcellulose with 0.2% (w/v) sodium dodecyl sulphate) at different ratios to carry out the precipitation step. IBP-IPA-Water composition was selected from ternary diagram for a highly supersaturated zone to obtain smaller size particles. The mean particle size [d(0.5)] obtained by this process (300nm) was much smaller when compared to that obtained from the decoupled process (1.5µm). Optimization of the solvent-anti-solvent ratio and drug concentration was necessary to achieve a smaller particle size. PXRD and DSC results revealed that the solid state properties of the original IBP and the prepared NC samples by cavi-precipitation samples were similar.

Application of the combinative particle size reduction technology H 42 to produce fast dissolving glibenclamide tablets.

Standard particle size reduction techniques such as high pressure homogenization or wet bead milling are frequently used in the production of nanosuspensions. The need for micronized starting material and long process times are their evident disadvantages. Combinative particle size reduction technologies have been developed to overcome the drawbacks of the standard techniques. The H 42 combinative technology consists of a drug pre-treatment by means of spray-drying followed by standard high pressure homogenization. In the present paper, spray-drying process parameters influencing the diminution effectiveness, such as drug and surfactant concentration, were systematically analyzed. Subsequently, the untreated and pre-treated drug powders were homogenized for 20 cycles at 1500 bar. For untreated, micronized glibenclamide, the particle size analysis revealed a mean particle size of 772 nm and volume-based size distribution values of 2.686 µm (d50%) and 14.423 µm (d90%). The use of pre-treated material (10:1 glibenclamide/docusate sodium salt ratio spray-dried as ethanolic solution) resulted in a mean particle size of 236 nm and volume-based size distribution values of 0.131 µm (d50%) and 0.285 µm (d90%). These results were markedly improved compared to the standard process. The nanosuspensions were further transferred into tablet formulations. Wet granulation, freeze-drying and spray-drying were investigated as downstream methods to produce dry intermediates. Regarding the dissolution rate, the rank order of the downstream processes was as follows: Spray-drying>freeze-drying>wet granulation. The best drug release (90% within 10 min) was obtained for tablets produced with spray-dried nanosuspension containing 2% mannitol as matrix former. In comparison, the tablets processed with micronized glibenclamide showed a drug release of only 26% after 10 min. The H 42 combinative technology could be successfully applied in the production of small drug nanocrystals. A nanosuspension transfer to tablets that maintained the fast dissolution properties of the drug nanocrystals was successfully achieved.

Performance comparison of two novel combinative particle-size-reduction technologies.

The nanosizing of poorly soluble drugs as a formulation strategy can eventually enhance their dissolution rate and bioavailability. Standard comminution techniques such as high-pressure homogenization (HPH) or wet bead milling have limitations in reaching the desired mean particle size. Combinative methods have been developed to overcome these limitations. Combinations of a bottom-up step (freeze-drying or spray drying) with HPH (the so-called H 96 and H 42 technologies, respectively) are examples of combinative particle-size-reduction technologies. The precipitation step modifies the drug structure to obtain a brittle starting material for the following homogenization process. Previous experiments using the H 96 technology have shown a relation between the bottom-up conditions and the final particle size after the top-down step. Employing the H 42 process, the poorly soluble drug glibenclamide was dissolved in ethanol, containing different amounts of surfactant. The drug solution was then spray dried. Subsequently, the drug powders were homogenized using the HPH technique. The nanosuspensions produced with the spray-dried powders (high drug concentrations, standard surfactant concentration) had a smaller particle size and a narrower size distribution compared with the unmodified drug. The best sample had a 236 nm mean particle size (observed using photon correlation spectroscopy) and laser diffractometry values of 0.131 µm (D50) and 0.285 µm (D90) after 20 cycles of homogenization. The results were compared with the reduction effectiveness of a previous study employing the H 96 combinative process. Both combinative technologies can be successfully applied for the production of very small drug nanocrystals.

Bottom-up approaches for preparing drug nanocrystals: formulations and factors affecting particle size.

The solubility dependent bioavailability problem has become a major hurdle in drug development processes. Drug nanocrystals have been widely accepted by the pharmaceutical industry to improve the bioavailability of poorly water-soluble compounds. Top-down and bottom-up technologies are the two primary technical approaches of drug nanocrystal production. Though the top-down approach has been hugely successful on the commercial front, it has some inherent drawbacks that necessitate the emergence of alternate approaches. The bottom-up approach has not yet been established as a successful commercial technology. However, it has the potential to produce small size drug nanocrystals with less energy demanding processes. The bottom-up approach is commonly known as precipitation technique. It would be possible to stabilize particles at an early stage of precipitation and to generate drug nanocrystals. In the first part of this review article, we have discussed various bottom-up technologies that are currently in use. This has been followed by description and analysis of various process parameters that can affect the final particle size of the drug nanocrystals.

Factors influencing the release kinetics of drug nanocrystal-loaded pellet formulations.

CONTEXT: This article discusses the downstream processing of nanosuspensions into oral solid dosage forms. OBJECTIVE: Various factors influencing the release kinetics of various pellet formulations containing drug nanocrystals have been evaluated. The effects of binder types, drug content and pellet type on the in-vitro dissolution profiles were investigated. MATERIALS AND METHODS: Hydrocortisone acetate (HCA) was nanosized by using a piston gap homogenizer Micron Lab 40. The nanosuspension was admixed to various binder solutions based on chitosan chloride, polyvinyl alcohol, hydroxypropyl methylcellulose or polyvinylpyrrolidone (PVP) and sprayed on sugar beads using fluidized bed coating. For comparison, matrix cores have also been prepared using the extrusion-spheronization process. An enteric top coating was applied onto both pellet types. All pellet formulations have been tested In in-vitro dissolution studies. RESULTS AND DISCUSSION: HCA nanosuspensions were compatible with all binders tested except for PVP. Various suspensions could be successfully transferred into spray coated pellets as well as matrix cores including a top coating. The different binder types have influenced the stability of the nanosuspensions, the zeta potential of the drug nanocrystals as well as the dissolution profiles of the final solid dosage forms. CONCLUSION: Nanosuspensions can be easily processed into various pellet formulations. Spray coating with water-soluble binders is recommended for high dose drugs. This technology is also more variable with respect to the drug load In the final dosage form. Matrix cores can be beneficial for highly water-insoluble formulations, especially when only relatively low doses are needed.

Drug nanocrystals in the commercial pharmaceutical development process.

Nanosizing is one of the most important drug delivery platform approaches for the commercial development of poorly soluble drug molecules. The research efforts of many industrial and academic groups have resulted in various particle size reduction techniques. From an industrial point of view, the two most advanced top-down processes used at the commercial scale are wet ball milling and high pressure homogenization. Initial issues such as abrasion, long milling times and other downstream-processing challenges have been solved. With the better understanding of the biopharmaceutical aspects of poorly water-soluble drugs, the in vivo success rate for drug nanocrystals has become more apparent. The clinical effectiveness of nanocrystals is proven by the fact that there are currently six FDA approved nanocrystal products on the market. Alternative approaches such as bottom-up processes or combination technologies have also gained considerable interest. Due to the versatility of nanosizing technology at the milligram scale up to production scale, nanosuspensions are currently used at all stages of commercial drug development, Today, all major pharmaceutical companies have realized the potential of drug nanocrystals and included this universal formulation approach into their decision trees.

Nanocrystals: comparison of the size reduction effectiveness of a novel combinative method with conventional top-down approaches.

Nanosizing is a non-specific approach to improve the oral bioavailability of poorly soluble drugs. The decreased particle size of these compounds results in an increase in surface area. The outcome is an increased rate of dissolution, which can lead to a better oral absorption. Standard approaches are bottom-up and top-down techniques. Combinative technologies are relatively new approaches, and they can be described as a combination of a bottom-up process followed by a top-down step. The work presented in this paper can be described as a combination of a non-aqueous freeze drying step (bottom-up), followed by wet ball milling or high pressure homogenization (top-down) to produce fine drug nanocrystals. The crystal habit of the model drug glibenclamide was modified by freeze drying from dimethyl sulfoxide (DMSO)/tert-butanol (TBA) solvent mixtures using different ratios. The resulting drug powders were characterized by scanning electron microscopy (SEM) as well as by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). It was shown that the combinative approach can significantly improve the particle size reduction effectiveness of both top-down methods over conventional approaches. Drug lyophilization using DMSO:TBA in 25:75 and 10:90 v/v ratios resulted in a highly porous and breakable material. The milling time to achieve nanosuspensions was reduced from 24h with the jet-milled glibenclamide to only 1h with the modified starting material. The number of homogenization cycles was decreased from 20 with unmodified API to only 5 with the modified drug. The smallest particle size, achieved on modified samples, was 160nm by wet ball milling after 24h and 355nm by high pressure homogenization after 20 homogenization cycles at 1500bar.

Process optimization of a novel production method for nanosuspensions using design of experiments (DoE).

Particle size reduction is a suitable method to enhance the bioavailability of poorly soluble drugs. The reduction effectiveness depends on compound properties like crystallinity, hardness and morphology. Sometimes, it is difficult to obtain small particles. To solve this problem a combinative method was developed: a combination of freeze drying with high pressure homogenization (so-called H 96 process). The freeze drying modifies the drug structure to obtain a brittle, fragile starting material for the subsequent homogenization step. Screening experiments with glibenclamide have shown a relation between the lyophilization conditions and the final particle size. Systematic investigations using design of experiment (DoE) were conducted to identify optimal process parameters. The influence of the independent variables drug concentration and organic solvent composition during freeze drying were tested by conducting a two factorial design of experiment. The model drug was dissolved in mixtures of dimethyl sulfoxide (DMSO) and tert-butanol (TBA) in different concentrations, freeze dried and subsequently homogenized at high pressure. Using optimized process conditions the particle size after 20 cycles was very small: 164 nm (z-average) and 0.114 µm (d50%). On the contrary, with unmodified drug the results were 772 nm (z-average) and 2.686 µm (d50%). It was shown, that the structure modification of the drug by means of freeze drying can significantly improve the particle size reduction effectiveness of high pressure homogenization. The study confirmed also the usefulness of DoE for nanocrystal production.