Rajan Jog

Pharmaceutical Amorphous Nanoparticles

There has been a tremendous revolution in the field of nanotechnology, resulting in the advent of novel drug delivery systems known as nanomedicines for diagnosis and therapy. One of the applications is nanoparticulate drug delivery systems which are used to improve the solubility and oral bioavailability of poorly soluble compounds. This is particularly important because most of the molecules emerging from the drug discovery pipeline in recent years have problems associated with solubility and bioavailability. There has been considerable focus on nanocrystalline materials; however, amorphous nanoparticles have the advantage of synergistic mechanisms of enhancing dissolution rates (due to their nanosize range and amorphous nature) as well as increasing supersaturation levels (due to their amorphous nature). An example of this technology is NanomorphTM, developed by Soliqus/Abbott, wherein the nanosize drug particles are precipitated in an amorphous form in order to enhance the dissolution rate. This along with other simple and easily scalable manufacturing techniques for amorphous nanoparticles is described. In addition, the mechanisms of formation of amorphous nanoparticles and several physicochemical properties associated with amorphous nanoparticles are critically reviewed.

In Vitro and In Vivo Performance of Different Sized Spray-Dried Crystalline Itraconazole

The objectives of the present study were to formulate and optimize different sized liquid and solid nanocrystalline formulations and evaluate their in vitro and in vivo performance to determine the effect of particle size on the oral bioavailability of solid nanocrystalline formulations. Nanotechnology is a promising approach to solve the problem of poor oral bioavailability of Biopharmaceutical Classification System class II/IV compounds. However, the highly exposed surface area of nanocrystals and hence their high Gibbs free energy poses a great challenge to nanocrystalline suspension stabilization. In this study, stabilization was achieved by preparing spray-dried nanocrystalline powders. A design of experiment approach was utilized to optimize the nanocrystalline suspensions/powders. On the basis of drug solubility studies, polyvinylpyrrolidone 40 KDa and sodium lauryl sulfate were selected for wet milling processing. Mannitol was chosen as the auxiliary excipient for spray-drying processing. In vitro dissolution utilizing a United States Pharmacopeia (USP) apparatus II showed superior release profiles for both liquid and nanocrystalline powder formulations compared with coarse-sized and unmilled formulations. Significantly, the oral bioavailability of nanocrystalline formulations with particle size of 280 nm was more than 20 times that of the unmilled formulation, whereas the nanocrystalline formulation with particle size of 750 nm showed only a 2.8 times increase in bioavailability compared with the unmilled formulation.

Solid state drug-polymer miscibility studies using the model drug ABT-102

Amorphous solid dispersions typically suffer storage stability issues due to: their amorphous nature, high drug loading, uneven drug:stabilizer ratio and plasticization effects as a result of hygroscopic excipients. An extensive solid state miscibility study was conducted to aid in understanding the mechanisms involved in drug/stabilizer interactions. ABT-102 (model drug) and nine different polymers with different molecular weights and viscosities were selected to investigate drug/polymer miscibility. Three different polymer:drug ratios (1:3, 1:1 and 3:1, w/w) were analyzed using: DSC, FTIR and PXRD. Three different techniques were used to prepare the amorphous solid dispersions: serial dilution, solvent evaporation and spray drying. Spray drying was the best method to obtain amorphous solid dispersions. However, under certain conditions amorphous formulations could be obtained using solvent evaporation. Melting point depression was used to calculate interaction parameters and free energy of mixing for the various drug polymer mixtures. The spray dried solid dispersions yielded a negative free energy of mixing which indicated strong drug-polymer miscibility compared to the solvent evaporation and serial dilution method. Soluplus was the best stabilizer compared to PVP and HPMC, which is probably a consequence of strong hydrogen bonding between the two CO moieties of soluplus and the drug NH moieities.

Formulation and Performance of Danazol Nano-crystalline Suspensions and Spray Dried Powders

ABSTRACTPurposeThis study focuses on the formulation optimization, in vitro and in vivo performance of differently sized nano-crystalline liquid suspensions and spray-dried powders of a poorly soluble BCS class II compound i.e. Danazol.MethodsA DoE approach was utilized to optimize stabilizer concentration and formulate danazol (BCS class II) nano-crystalline suspensions and dry powders via wet milling followed by spray drying. Solubility studies were performed to select best stabilizers. Particle size, PXRD, contact angle measurement and in vitro dissolution were utilized in characterization of the liquid and spray-dried powder formulations.ResultsThe liquid nano-crystalline suspensions followed particle size-dependent dissolution rates i.e. faster dissolution for smaller crystals. The spray-dried nano-crystal powders did not show fast dissolution profiles compared to the liquid nano-crystalline suspension. The poor dissolution of the spray-dried powder correlated to its high LogP value (i.e. LogP 4.53) and poor wetting (or polar surface-area). In vivo bioavailability studies showed superior performance of the liquid nano-crystalline suspensions compared to other milled and un-milled formulations.ConclusionWet-milling and spray-drying optimization for danazol nano-crystalline suspension was performed. This study indicates that drug candidates with high LogP values and low polar surface area may not be suitable for formulation as dry nano-crystals.

Formulation design and evaluation of amorphous ABT-102 nanoparticles.

Amorphous nanoparticles are able to enhance the kinetic solubility and concomitant dissolution rates of BCS class II and BCS class II/IV molecules due to their characteristic increased supersaturation levels, smaller particle size and greater surface area. A DoE approach was applied to investigate formulation and spray drying process parameters for the preparation of spray dried amorphous ABT-102 nanoparticles. Stability studies were performed on the optimized formulations to monitor physical and chemical changes under different temperature and humidity conditions. SLS/soluplus and SLS/PVP K25 were the best stabilizer combinations. Trehalose was used to prevent nanoparticle aggregation during spray drying. Particle size distribution, moisture content, PXRD, PLM, FTIR and in vitro dissolution were utilized to characterize the spray dried nanoparticle formulations. The formulations prepared using soluplus showed enhanced dissolution rate compared to those prepared using PVP K25. Following three months storage, it was observed that the formulations stored at 4°C were stable in terms of particle size distribution, moisture content, and crystallinity, whereas those stored at 25°C/60%RH and 40°C/75%RH were unstable. A predictive model to prepare stable solid spray dried amorphous ABT-102 nanoparticles, incorporating both formulation and process parameters, was successfully developed using multiple linear regression analysis.

Physicochemical attributes and dissolution testing of ophthalmic ointments

The investigation of semisolid ophthalmic ointments is challenging due to their complex physicochemical properties and the unique anatomy of the human eye. Using Lotemax® as a model ophthalmic ointment, three different manufacturing processes and two excipient sources (Fisher® (OWP) and Fougera® (NWP)) were used to prepare loteprednol etabonate ointments that were qualitatively and quantitatively the same across the manufactured formulations. Physicochemical properties including drug content and uniformity, particle size and distribution, as well as rheological parameters (onset point, crossover modulus, storage modulus and Power law consistency index) were investigated. In addition, USP apparatus 2 with enhancer cells was utilized to study the in vitro drug release characteristics of the ophthalmic ointments. Both manufacturing processes and excipient sources had a significant influence on the physicochemical attributes and the in vitro drug release profiles of the prepared ointments. Ointments prepared via the hot melt processes exhibited higher rheological parameters and lower drug release rates compared to ointments prepared without hot melting. Ointments prepared with OWP demonstrated higher rheological parameters and lower in vitro drug release rates compared to ointments prepared with NWP. A strong correlation between the rheological parameters and in vitro drug release rate was shown using logarithmic linear regression. This correlation may be useful in predicting in vitro drug release from measured physicochemical properties, and identifying the critical quality attributes during the development of ointment formulations.

Formulation design space for stable, pH sensitive crystalline nifedipine nanoparticles

Enteric coated formulations protect drugs from degrading in the harsh environment of the stomach (acidic pH and enzymes), and promotes drug delivery to and absorption into the duodenum and/or later parts of the intestine. Four DoE models were applied to optimize formulation parameters for the preparation of pH sensitive nifedipine nanoparticles. Stability studies were performed on the optimized formulations to monitor any possible variation in particle size distribution, homogeneity index, surface charge and drug release (pH 1.2 and pH 6.8). Stability studies were performed for 3 months at 4°C, 25°C and 40°C. A combination of Eudragit®L 100-55 and polyvinyl alcohol was determined to be the most effective in stabilizing the nanoparticle suspension. The average particle size distribution, polydispersity index and surface charge of the optimized pH sensitive nifedipine nanoparticles were determined to be 131.86±8.21nm, 0.135±0.008 and -7.631±0.146mV, respectively. Following three months storage, it was observed that the formulations stored at 4°C were stable in terms of particle size distribution, polydispersity index, surface charge, drug loading and drug release, whereas those stored at 25°C and 40°C were relatively unstable. A predictive model to prepare stable pH sensitive nifedipine nanoparticles, was successfully developed using multiple linear regression analysis.

Nanoamorphous drug products – Design and development

&NA; Most of the recent drug compounds coming out of the drug discovery pipeline are labile (multiple polymorphs), and need to be developed into robust marketed oral drug formulations. There are only 22 oral macroamorphous drug products approved by FDA and till date none approved oral nanoamorphous drug products. However, there are several oral nanoamorphous drug formulations (including both labile and non‐labile drugs) being researched and a few of these are in the clinical trials. Due to the labile nature of these drug compounds, there is a need to utilize a controlled strategy for design and development of robust nanoamorphous drug formulations in order to prevent any physicochemical instability. The present research focuses on the use of a novel integrated critical process parameters and critical formulation parameters (iCPP‐CFPs) DoE approach for the design and development of stable nanoamorphous spironolactone (BCS class II compound with eight polymorphic forms). There are possibilities of the interconversion of these polymorphic forms during processing (manufacturing nanoamorphous particles) and during storage. In the present study, polymorphic transitions (amorphous to crystalline and anhydrous to hydrate) were carefully monitored via orthogonal solid‐state characterization tools. Significant polymorphic transitions were observed in the formulations stored at 40 °C/75% RH over six months, however the formulations stored at 4 °C were stable. The significant iCPP‐CFPs (solvent‐to‐antisolvent ratio, drug concentration and inlet temperature of the spray dryer) were critically investigated for their influence on different CQAs (critical quality attributes). Solvent‐to‐antisolvent ratio and inlet temperature were identified to be the significant iCPP‐CFPs. Particle size and total product yield were identified to be the significant CQAs. Lab‐scale manufacturing of the spray dried nanoamorphous spironolactone resulted in a remarkably high total product yield (82.4 ± 3.91% w/w) with a uniform and homogenous particle size (244.2 ± 23.32 nm). Furthermore, the physicochemical attributes and the drug release criteria of the nanoamorphous spironolactone were compared with two marketed products (spironolactone tablets, USP 100 mg (Pfizer and Mylan)) and other in‐house formulations. In addition, nanoamorphous spironolactone showed a significantly superior kinetic solubility/dissolution rate (10‐fold) with a longer supersaturation time (˜6h) compared to the in‐house formulations.