Solid Drug Particles Research Articles

The Key Role of Wettability and Boundary Layer in Dissolution Rate Test.

The present work proposes a mathematical model able to describe the dissolution of poly-disperse drug spherical particles in a solution (Dissolution Rate Test-DRT). DRT is a pivotal test performed in the pharmaceutical field to qualitatively assess drug bioavailability. The proposed mathematical model relies on the key hallmarks of DRT, such as particle size distribution, solubility, wettability, hydrodynamic conditions in the dissolving liquid of finite dimensions, and possible re-crystallization during the dissolution process. The spherical shape of the drug particles was the only cue simplification applied. Two model drugs were considered to check model robustness: theophylline (both soluble and wettable) and praziquantel (both poorly soluble and wettable). The DRT data analysis within the proposed model allows us to understand that for theophylline, the main resistance to dissolution is due to the boundary layer surrounding drug particles, whereas wettability plays a negligible role. Conversely, the effect of low wettability cannot be neglected for praziquantel. These results are validated by the determination of drug wettability performed while measuring the solid-liquid contact angle on four liquids with decreasing polarities. Moreover, the percentage of drug polarity was determined. The proposed mathematical model confirms the importance of the different physical phenomena leading the dissolution of poly-disperse solid drug particles in a solution. Although a comprehensive mathematical model was proposed and applied, the DRT data of theophylline and praziquantel was successfully fitted by means of just two fitting parameters.

Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments.

Additive-controlled crystallization is a promising method to improve crystal morphology and produce solid drug particles with the desired technological and pharmacological properties. However, its adaptation to continuous operation is a hardly researched area. Accordingly, in this work, we aimed to come up with a methodology that provides the systematic and fast development of a continuous three-stage MSMPR cascade crystallizer. For that, a cooling crystallization of famotidine (FMT) from water, in the presence of a formulation additive, poly(vinylpyrrolidone) (PVP-K12), was developed. Process parameters with a significant impact on product quality and quantity were examined in batch mode through a 24-1 fractional factorial design for the implementation of additive-controlled continuous crystallization. These batch experiments represented one residence time of the continuous system. Based on the statistical analysis, the residence time (RT) had the highest effect on yield, while the polymer amount was critical from the product polymorphism, crystal size, and flowability points of view. The values of critical process parameters in continuous operation were fixed according to the batch results. Two continuous cooling crystallization experiments were carried out, one with 1.25 w/wFMT% PVP-K12 and one with no additive. A mixture of FMT polymorphs (Form A and Form B) crystallized without the additive through five residence times (>6.5 h) with 70.8% overall yield. On the other hand, the additive-controlled continuous experiment resulted pure and homogeneous Form A product with excellent flowability. The system could be operated for >6.5 h without clogging with a 71.1% overall yield and a 4-fold improvement in productivity compared to its batch equivalent.

Preparing dry powder inhalation formulation of salbutamol sulfate using an ultrasonic atomizer device

Inhaled particles must possess certain morphological characteristics to ensure effective drug delivery to the targeted site in the lungs. A modified version of ultrasonic spray pyrolysis was employed to prepare salbutamol sulfate in the form of dry powder. A solution of salbutamol sulfate was atomized using ultrasonic nebulization, and the droplets were transformed into solid drug particles through exposure to high temperature airflow. The engineered salbutamol sulfate samples underwent physical characterization, including particle size, morphology, thermal behavior, and crystallinity analysis. The aerodynamic particle size distribution (APSD) and in vitro deposition of the dry powder inhalation formulation were assessed using the Next Generation Impactor (NGI). The salbutamol sulfate dry powder prepared by the ultrasonic atomizer exhibited an aerodynamic diameter ranging from 1 to 5 μm, as supported by the SEM images. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) results showed a significant drop in the crystallinity of the engineered particles. Aerosolization performance studies demonstrated a fine particle fraction (FPF) value (below 5 μm) of 25% for the engineered salbutamol sulfate produced using the ultrasonic atomizer technique, which is acceptable for inhalation purposes. Based on the observed results, this newly introduced method appears to be suitable for producing dry powder formulations of different drugs, with a minimized need for the use of surfactants or stabilizers in the formulation.

Nanosuspension: A Novel Approach to Improve the Solubility, Bioavailability and Pharmacokinetics of Poorly Soluble Drugs

Solubility is an essential factor for drug effectiveness, independent of the route of administration. Poorly water soluble drugs show major problems for drug formulation. Many conventional methods exist to address the issues of poor solubility and bioavailability, but they have many drawbacks. Nanotechnology is employed to address the issues related to these traditional methods for improving solubility and bioavailability. Pharmaceutical nanosuspension is a very finely colloid, biphasic, dispersed, solid drug particles in an aqueous vehicle, size below 1µm, without any matrix material, stabilised by surfactants and polymers, prepared by suitable methods for Drug Delivery applications, through various routes of administration such as oral, topical, parenteral, ocular and pulmonary routes. This article covers the advantages, disadvantages, properties, preparation of nanosuspension by bottom up technology, top down technology, melt emulsification, emulsification- solvent evaporation and supercritical fluid with their advantages and disadvantages, evaluation, and their drug delivery applications.

Review on Nanosuspension as a Novel Method for Solubility and Bioavailability Enhancement of Poorly Soluble Drugs

The formulation development of a drug is majorly based on the solubility of drugs. Nearly 40% of newly developed drugs show poor water solubility. Several approaches are used for the increasing solubility of such drugs for formulation development. Nanosuspension is one such attractive tactic which can be used for the enhancement of solubility, stability as well as bioavailability of such drugs. Nanosuspension can be defined as a two-phasic dosage form where solid drug particles of size less than 1 μm are dispersed in an aqueous phase with the help of a stabilizer. Particle size reduction in the nanoscale causes an increase in the surface area leading to an increase in dissolution rate and ultimately bioavailability is increased. A variety of excipients are used for the formulation of nanosuspension. Stabilizers, surfactants, co-surfactants, natural as well as organic solvents, buffers, salts, polyols, osmogents, and cryoprotectants are used in the formulation of nanosuspension. Various methods used in the formulation of nanosuspension can be classified into top-down and bottom-up approaches. Wet milling, high-pressure homogenization, anti-solvent techniques, melt emulsification, supercritical fluid extraction and ultrasonic homogenization are some of the methods for the preparation of nanosuspension. These methods are easy and appropriate for all poor water-soluble drugs. Nanosuspensions technology can be applied for the preparation of oral, pulmonary, injectable, ocular as well as targeted drug delivery. This review emphasizes various advantages and disadvantages of nanosuspension, its methods of preparation, formulation approaches, evaluation parameters, pharmaceutical applications, marketed products and patents of nanosuspension.

The Effects of Solid Particle Containing Inks on the Printing Quality of Porous Pharmaceutical Structures Fabricated by 3D Semi-Solid Extrusion Printing

PurposeSemi-solid extrusion (SSE) 3D printing has potential pharmaceutical applications for producing personalised medicine. However, the effects of ink properties and drug incorporation on the quality of printed medication have not been thoroughly studied, particularly for porous geometries. This study aimed to investigate the effects of the presence of solid drug particles in SSE inks on the printing quality of porous structures.MethodThe rheological behaviour of model inks of paracetamol (PCM)-hypromellose (HPMC) with different drug loadings were investigated and correlated to their printing qualities.ResultsFor the inks with PCM loading above the drug solubility in which suspended solid drug particulates were present, the results confirmed that PCM loading and particle size significantly affected the ink viscosities at a low shear rate. At a low shear rate, the highest viscosity was identified when the highest drug loading and the smallest PCM particles were incorporated into the inks. However, the results indicated that the SSE printing parameters and printing quality of porous structures (with less porous structural deformation) have no clear correlation with the shear viscosity data, but a strong correlation with the dynamic oscillatory rheology of the inks.ConclusionThe key rheological parameters including storage modulus, loss modulus and complex viscosity of the ink increased with increasing drug loading for the inks containing solid drug particles. However, decreasing the particle size did not have a clear effect on the oscillatory rheology of the inks which can be potentially used for optimising the SSE 3D printing quality of porous geometries.

An impact of nanocrystals on dissolution rate of Lercanidipine: Supersaturation and crystallization by addition of solvent to antisolvent

BackgroundNanocrystals of any drug are pure solid drug particles with a mean diameter in nanometer range. Dissolution is a crucial factor for absorption of medicine in case of water-insoluble or poorly soluble drugs. The aim of this study was to develop nanocrystals of a hydrophobic drug, Lercanidipine, by addition of solvent to an antisolvent with high-speed homogenization to achieve dissolution and solubility enhancement. Addition of organic solvent to antisolvent results in genesis of nanosized particles due to fast nucleation process and rapid mixing. The nanosuspension was formulated using PVP K30 as a stabilizer. Further, nanosuspensions were lyophilized to convert into solid nanocrystals using mannitol as a cryoprotectant. The developed nanosuspensions were characterized for particle size, zeta potential, saturation solubility, and in vitro dissolution studies. Lyophilized solid nanocrystals were characterized for FTIR, SEM, XRD, and zeta potential (ζ).ResultsCentral composite design was executed to study influence of amount of stabilizer and solvent to antisolvent ratio (independent variables) on particle size and % drug release at 10 min (dependent variables). The particle size of the developed Lercanidipine nanosuspensions were observed in the range of 302.00 ± 10.58 to 484.33 ± 6.51 nm measured by Zetatrac. A considerable increase was found in the solubility and dissolution rate of the nanocrystals as compared to pure drug. The drug release from Lercanidipine nanosuspensions was increased up to 88.95% within 10 min as compared to pure Lercanidipine which was only 21.53%. The X-ray diffraction study of lyophilized nanocrystals showed sharp and distinct peaks due to an increse in crystallinity of Lercanidipine Particle morphology was studied by scanning electron microscopy revealed that nanoprecipitated particles with lyophilization in the presence of mannitol exhibited dendrite needle-like crystals.ConclusionThe nanocrystal development by antisolvent precipitation procedure using methanol as solvent, water as antisolvent, and low amounts of PVP K30 as stabilizer is a very promising and effective method to increase the dissolution rate of Lercanidipine.Graphical abstract

Release behaviors and kinetics of coated bead‐on‐string nanofibrous multilayer membranes loaded with drug particles

AbstractA bead‐on‐string structure with special beads at the microscale level could act as an effective carrier for solid drug particles as well as giving a continuous and sustained release profile. Tetracycline hydrochloride (TCH), used as solid model drug particles, was ground to obtain nanoscale and well‐distributed size. Electrospun poly[lactic‐co‐(glycolic acid)] (PLGA) bead‐on‐string nanofibers loaded with TCH of different particle sizes were fabricated for controlled drug delivery. The morphology of TCH particles and bead‐on‐string nanofibers were observed using a particle sizer and scanning electron microscopy. The effects of drug particle size on the release behaviors of nanofibers were further investigated and analyzed using UV–visible spectrophotometry. In vitro release results suggested that bead‐on‐string nanofibers encapsulating ground TCH particles had higher total drug release quantity compared with unground particle‐loaded nanofibers. Coating of the surface of PLGA/TCH nanofibers was investigated for controlled‐release effects and the release mechanism to understand the drug–polymer carrier interaction. The results indicated that coating on both sides of nanofibrous membranes could effectively decrease the initial burst release. Bead‐on‐string nanofibers proved to be promising mats for drug delivery applications. © 2021 Society of Industrial Chemistry.

An Overview on Recent Advances in Pharmaceutical Suspensions

The suspension is a biphasic liquid or semi-solid dosage form where the finely divided insoluble solid drug particles are homogeneously dispersed in a liquid or semi-solid medium. The solid drug particles act here as the dispersed phase and the liquid or the semi-solid as the dispersion medium. The particle diameter in a suspension is usually greater than 0.5 µm. However, it is difficult and also impractical to impose a sharp boundary between the suspensions and the dispersions having finer particles. Suspensions are an important class of pharmaceutical dosage forms. The advantages of suspension dosage forms include effective dispensing of hydrophobic drugs; avoidance of the use of cosolvents; masking of unpleasant taste of certain ingredients; offering resistance to degradation of drugs due to hydrolysis, oxidation or microbial activity; easy swallowing for young or elderly patients; and efficient intramuscular depot therapy. In addition, when compared to solution dosage forms, relatively higher concentration of drugs can be incorporated into suspension products. The present review provides an overview of various aspects of suspensions such as classification of suspensions, theories of suspensions, various suspending agents, formulations aspects of suspensions, stability of suspensions and recent research work that is being carried on suspensions. Keywords: Suspensions, suspending agents, flocculated, Stability.

In vitro physicochemical characterization and dissolution of brinzolamide ophthalmic suspensions with similar composition.

The quality of an ophthalmic suspension is crucial for its in vivo performance, and often impact product's effectiveness. An in-depth understanding of critical quality attributes (CQAs) of ophthalmic suspensions such as particle size distribution (PSD) and rheology, as well as the impact of these CQAs on product performance are important for successful product development, quality control, and regulatory approval. This study employed brinzolamide ophthalmic suspension, 1%, as a model ophthalmic product, and six batches were manufactured using an innovative planetary centrifugal milling (PCM) process. Three batches were manufactured to have distinctly different PSD. These three batches had qualitatively (Q1) and quantitatively (Q2) the same composition as the model drug product (i.e., Azopt), while the differences in PSD were introduced by changing only the manufacturing process parameters. On the other hand, changes in rheology were introduced by altering the input level of the viscosity enhancing polymer in the formulation. A systematic approach was employed to understand the relation between manufacturing process parameters, CQAs, and in vitro product performance. Among the evaluated CQAs, PSD, rheology, surface tension, and drug dissolution were found more sensitive to the changes in the manufacturing processes. Most notably, we developed a rapid dissolution method (completed within minutes) employing in-situ fiber optic UV dissolution system. This novel dissolution method mimics the environmental conditions of the eye such as dissolution under "non-sink" condition and under high shear (from blinking). The method was highly discriminatory to differences in the PSD in the suspension. This study also revealed an important relation between the PSD of the suspension and its rheology which originated as a result of an interaction at the molecular level between the solid drug particles and the viscosity enhancing polymers. These findings underscore the need to evaluate CQAs of the ophthalmic suspensions in concert rather than separately when comparing ophthalmic drug products and product performance.

Nanosuspension Technology for Delivery of Poorly Soluble Drugs and Its Applications: A Review

Now a days, many drug candidates are water insoluble hence they show a limited drug release and poor bioavailability. It is difficult to formulate these drugs by conventional dosage form. Nanosuspension technology is a promising approach to solve the problems of poorly soluble and less bioavailable drugs. Nanosuspension is a very finely colloidal, biphasic, and uniformly dispersed solid drug particles in a suitable aqueous vehicle, having a particle size below 1 μm stabilized by suitable surface active agents and polymers. Nanosuspensions are prepared by various suitable techniques for drug delivery applications. Due to reduced particle size at the nano scale, surface area, saturation solubility, dissolution velocity and bioavailability of BCS class II and class IV drugs are increased sufficiently. Nanosuspension is suitable to administration via various routes such as oral, intravenous, topical, pulmonary and ocular delivery systems. Nanosuspension can be also used for targeting purpose in various diseases such as cancer, HIV and production of sustained and extended release products by choosing suitable polymers. Production and manufacturing are not complicated, easy to scale up. Top down and bottom technologies are used for the preparation of nanosuspensions. It includes methods such as high-pressure homogenization, by milling media method, precipitation method, probe sonication, dry-co-grinding, supercritical fluid method, and lipid emulsion method. Formulation consists of stabilizers, surfactant, and solvents. Nanosuspension can be stored in the form of dry powder using spray drying, freeze drying techniques. This review describes the advantages, various methods of preparation, formulation consideration and characterization of nanosuspension.

Experimental and mathematical study of the transdermal delivery of sumatriptan succinate from polyvinylpyrrolidone-based microneedles

A mechanistic model was developed and tested to predict the release of sumatriptan succinate from dissolving microneedles and its permeation across the epidermal skin layers. Material balance equations were written to describe molecular transport followed by absorption into the systemic circulation. The solid drug particles were encapsulated in pyramid-shaped, polyvinylpyrrolidone-based water-soluble microneedles. Plots, generated from literature values and designed to simulate concentration distributions in the epidermal layers, agreed with optical coherence tomography (OCT)images captured at early stages of the experiments. Simulations showed that an increase in the pitch width led to a faster release of the medication. By modifying the governing equations to include a microneedle baseplate, the model was able to estimate short- and long-term release behaviors from in vitro Franz cellexperiments. These studies were performed using three distinct dissolving microneedle formulations and minipig skin as the biological membrane. The calculated diffusion coefficients were one order of magnitude greater than the value estimated when the drug was directly applied to the skin surface. The dissolution rate constant was affected by the concentration of the polymer matrix.

Solid drug particles encapsulated bead-on-string nanofibers: the control of bead number and its corresponding release profile

Bead-on-string nanofibers are explored as potential carriers of micro-level solid drug particles in recent years in drug release and tissue engineering. The special alternating distribution of nanoscale fiber and micro beads satisfied the fully encapsulation of particle drugs and the corresponding sustained release. Antibiotic drug tetracycline hydrochloride (TCH) was used as solid model drug particles. The present study fabricated poly (lactic-co-glycolic acid) (PLG A) bead-on-string nanofibers with different TCH loading rates for the controlled drug delivery. Bead number (BN), as one of the crucial factors that determine the encapsulation capability, was successfully controlled by tailoring the electrospinning parameters: voltage, flow rate and distance. The in vitro release experiment analyze by UV-Visible light spectrophotometer indicated that the bead-on-string nanofiber with more BN would increase the total release quantity of TCH. The drug released from bead-on-string nanofibers was mainly driven by classical Fickian diffusion. PLGA bead-on-string nanofibers suggest the potential as promising substrate for solid drug particles delivery applications.

A novel technique for intraduodenal administration of drug suspensions/solutions with concurrent pH monitoring applied to ibuprofen formulations

Characterization of dissolution of solid suspended drug particles in vivo is important for developing biopredictive in vitro tests. Therefore, methods to gain deeper insights into particle dissolution in vivo are needed. The soft Bioperm intubation method, a well established tool for investigation of permeability, absorption, metabolism, and drug interactions at predefined locations in the gastroinstinal tract, was modified. The novel intubation method involved pump-controlled infusion of pharmaceutical suspensions as well as simultaneous pH monitoring. This technique was used in a proof of concept study in healthy humans. Plasma sampling and non-compartmental analysis allowed comparison of three different ibuprofen drug products, a solution and two suspensions with different particle size distribution, as well as two different infusion rates. Both a particle size effect and an effect of altering infusion rates on pharmacokinetic parameters were shown. Moreover, it was possible to monitor intestinal pH changes after intestinal infusion. Infusion of ibuprofen resulted in a pH drop that was quantified by the concept of Area Between Curves (ABC).

A combined mathematical model linking the formation of amorphous solid dispersions with hot-melt-extrusion process parameters

Hot-melt extrusion allows for the continuous production of amorphous solid dispersions, which are used to enhance bioavailability of poorly soluble drugs in pharmaceutical drug delivery. To facilitate formulation and extrusion process development, we propose a mathematical model describing the formation of amorphous solid dispersions in the context of this process. The model is based on the calculation of two key process values: (1) time to dissolution of solid drug particles in molten polymer during extrusion and (2) mean residence of material in the extruder. We suggest that their linking allows for rational process design. Experimental data support the validity of our model for both key process values as well as the overall process. This modeling approach allows for fast and cost-effective formulation and extrusion process development as well as feasibility estimations in early stages of drug development.

Design Space and QbD Approach for Production of Drug Nanocrystals by Wet Media Milling Techniques.

Drug nanocrystals are nanosized solid drug particles, the most important application of which is the improvement of solubility properties of poorly soluble drug materials. Drug nanocrystals can be produced by many different techniques, but the mostly used are different kinds of media milling techniques; in milling, particle size of bulk sized drug material is decreased, with the aid of milling beads, to nanometer scale. Utilization of Quality by Design, QbD, approach in nanomilling improves the process-understanding of the system, and recently, the number of studies using the QbD approach in nanomilling has increased. In the QbD approach, the quality is built into the products and processes throughout the whole production chain. Definition of Critical Quality Attributes, CQAs, determines the targeted final product properties. CQAs are confirmed by setting Critical Process Parameters, CPPs, which include both process parameters but also input variables, like stabilizer amount or the solid state form of the drug. Finally, Design Space determines the limits in which CPPs should be in order to reach CQAs. This review discusses the milling process and process variables, CPPs, their impact on product properties, CQAs and challenges of the QbD approach in nanomilling studies.

FORMULATION AND BIO-AVAILABILITY PARAMETERS OF PHARMACEUTICAL SUSPENSION

The suspension is a biphasic liquid or semi-solid dosage form where the finely divided insoluble solid drug particles are homogeneously dispersed in a liquid or semi-solid medium. The solid drug particles act here as the dispersed phase and the liquid or the semi-solid as the dispersion medium. Suspensions contribute to pharmaceutical dosage form development by supplying drugs that are insoluble in all acceptable medium and often distasteful. Suspension translates such drugs into more bio-available form when compared to capsules, tablets, coated tablets, enteric coated tablets and sustained release products. The dosage form is palatable to the patient and many are doing well when applied to the skin or mucous membrane. This particular dosage form is also applied for injecting drugs into the systemic circulation. Therefore, pharmaceutical suspension finds its application through three different routes of administration namely oral, externally applied suspension and injectable one. The success of any dosage form largely depends on formulation parameters and the factors that influence the bioavailability which ultimately dictate the therapeutic success of the formulated dosage form. Hence, it is obvious to discuss the formulation parameters and the factors influencing bioavailability of suspension for the therapeutic success of it.

Developing nanocrystals for cancer treatment.

Nanocrystals are carrier-free solid drug particles that are sized in the nanometer range and have crystalline characteristics. Due to high drug loading (as high as 100%) - free of organic solvents or solubilizing chemicals - nanocrystals have become attractive in the field of drug delivery for cancer treatment. Top-down and bottom-up approaches have been developed for preparing anticancer nanocrystals. In this review, preparation methods and in vivo performance of anticancer nanocrystals are discussed first, followed by an introduction of hybrid nanocrystals in cancer theranostics.

Solid state transformations in consequence of electrospraying – A novel polymorphic form of piroxicam

The aim of the research was to verify that electrospraying of piroxicam yielded a new polymorphic form of this drug. In the experiments, piroxicam was dissolved in chloroform and the solution was atomised electrostatically. Subsequently, the charged droplets were neutralised and dried. The solid drug particles were collected and analysed by scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, high performance liquid chromatography, and infrared and Raman spectroscopy. The X-ray diffractogram measured for the electrosprayed piroxicam particles did not match with any of the known piroxicam crystal structures (Cambridge Crystallographic Data Centre). The variable temperature X-ray diffraction showed that the structure recrystallised completely into piroxicam polymorphic formI during heating. No degradation products or solvate removal was detected by high performance liquid chromatography and thermal analysis. The infrared and Raman spectra of the electrosprayed piroxicam were compared to those of formI, and some notable differences in the peak positions, shapes and intensities were detected. The results indicate that electrospraying leads to piroxicam crystallisation in a currently unknown polymorphic form.

Nanosuspension: A Novel Drug Delivery System

Low bioavailability is the major problem associated with poorly soluble drugs. The problem is more complex for drugs which are poorly soluble in both aqueous and nonaqueous media, as solubility is an essential factor for drug absorption, independent of the route of administration. Nanosuspensions have emerged as an attractive and promising approach to improve stability and bioavailability of poorly soluble drugs. These are very finely colloid, biphasic, dispersed, solid drug particles in an aqueous vehicle, size below 1?m, without any matrix material, stabilized by surfactants and polymers. Techniques such as wet milling, high-pressure homogenization, emulsification-solvent evaporation and supercritical fluid have been used in the preparation of nanosuspension. Nanosuspension can be delivered by oral, parenteral, pulmonary and ocular routes. DOI: http://dx.doi.org/10.3329/ijpls.v2i4.17117 International Journal of Pharmaceutical and Life Sciences Volume 2, Issue 4: October 2013; 179-196