Trends in amorphous solid dispersion drug products approved by the U.S. Food and Drug Administration between 2012 and 2023.

Forty-eight (48) drug products (DPs) containing amorphous solid dispersions (ASDs) have been approved by the U.S. Food and Drug Administration in the 12-year period between 2012 and 2023. These DPs comprise 36 unique amorphous drugs. Ten (10) therapeutic categories are represented, with most DPs containing antiviral and antineoplastic agents. The most common ASD polymers are copovidone (49%) and hypromellose acetate succinate (30%), while spray drying (54%) and hot melt extrusion (35%) are the most utilized manufacturing processes to prepare the ASD drug product intermediate (DPI). Tablet dosage forms are the most common, with several capsule products available. Line extensions of several DPs based on flexible oral solids and powders for oral suspension have been approved which provide patient-centric dosing to pediatric and other patient populations. The trends in the use of common excipients and film coating types are discussed. Eighteen (18) DPs are fixed-dose combinations, and some contain a mixture of amorphous and crystalline drugs. The DPs have dose/unit of amorphous drug ranging from <5 mg up to 300 mg, with the majority being ≤100 mg/unit. This review details several aspects of DPI and DP formulation and manufacturing of ASDs, as well as trends related to therapeutic category, dose, and patient-centricity.

Mannitol-coated hydroxypropyl methylcellulose as an alternative directly compressible controlled release excipient.

One of the most common forms of controlled release technology for oral drug delivery comprises an active ingredient dispersed in a hydrophilic matrix forming polymer such as hydroxypropyl methylcellulose (HPMC), which is tableted via direct compression. However, HPMC may pose problems in direct compression due to its poor flowability. Hence, mannitol syrup was spray-coated over fluidized HPMC particles to produce co-processed HPMC-mannitol at ratios of 20:80, 50:50, and 70:30. Particles of pure HPMC, co-processed HPMC-mannitol, and their respective physical mixtures were evaluated for powder flowability, compression profiles, and controlled release performance. It was found that co-processed HPMC-mannitol consisted of particles with improved flow compared to pure HPMC particles. Sufficiently strong tablets of >2 MPa could be produced at moderate to high compression forces of 150-200 MPa. The dissolution profile could be tuned to obtain desired release profiles by altering HPMC-mannitol ratios. Co-processed HPMC-mannitol offers an interesting addition to the formulator's toolbox in the design of controlled release formulations for direct compression.

Nanomedicines for targeted pulmonary delivery: receptor-mediated strategy and alternatives.

Pulmonary drug delivery of nanomedicines is promising for the treatment of lung diseases; however, their lack of specificity required for targeted delivery limit their applications. Recently, a variety of pulmonary delivery targeting nanomedicines (PDTNs) has been developed for enhancing drug accumulation in lung lesions and reducing systemic side effects. Furthermore, with the increasing profound understanding of the specific microenvironment of different local lung diseases, multiple targeting strategies have been employed to promote drug delivery efficiency, which can be divided into the receptor-mediated strategy and alternatives. In this review, the current publication trend on PDTNs is analyzed and discussed, revealing that the research in this area has been attracting much attention. According to the different unique microenvironments of lung lesions, the reported PDTNs based on the receptor-mediated strategy for lung cancer, lung infection, lung inflammation and pulmonary fibrosis are listed and summarized. In addition, several other well-established strategies for the design of these PDTNs, such as charge regulation, mucus delivery enhancement, stimulus-responsive drug delivery and magnetic force-driven targeting, are introduced and discussed. Besides, bottlenecks in the development of PDTNs are discussed. Finally, we highlight the challenges and opportunities in the development of PDTNs. We hope that this review will provide an overview of the available PDTNs for guiding the treatment of lung diseases.

Influence of talc and hydrogenated castor oil on the dissolution behavior of metformin-loaded pellets with acrylic-based sustained release coating.

Multi-unit pellet system (MUPS) is of great interest as it is amenable to customization. MUPS comprises multi-particulates, usually as pellets or spheroids, which can be coated with diffusion barrier coatings. One commonly used diffusion barrier coating is the methacrylic acid copolymer, which can be used as a taste masking, enteric or sustained release polymer. While the versatility of methacrylic acid copolymers makes them pliable for pellet coating, there are impediments associated with their use. Additives commonly required with this polymer, including plasticizer and anti-adherent, have been shown to weaken the film strength. The objective of this study was to investigate the impact of osmotic pressure within the core on the sustained release coat integrity and functionality. Hydrogenated castor oil (HCO) was chosen as the additive to be studied. Metformin-loaded pellets, prepared via extrusion-spheronization, were coated with ethyl acrylate and methyl methacrylate copolymer (Eudragit RS 30 D) containing talc, talc-HCO, or HCO to different coat thicknesses. Drug release was investigated using the USP dissolution apparatus 2 and an ultraviolet imager. The swelling of the pellets when wetted was monitored by video imaging through a microscope. When coated to 7.5 % coat weight gain, coats with HCO slowed down drug release more than the other pellets. The pellets also swelled the most, which suggests that they were more resistant to the osmotic pressure exerted by metformin. For drugs which exert high osmotic pressure, HCO can serve as an efficient alternative to talc in the preparation of methacrylic acid copolymer coatings.

Formulation and Processing Strategies which Underpin Susceptibility to Matrix Crystallization in Amorphous Solid Dispersions.

Through matrix crystallization, an amorphous solid may transform directly into its more stable crystalline state, reducing the driving force for dissolution. Herein, the mechanism of matrix crystallization in an amorphous solid dispersion (ASD) was probed. ASDs of bicalutamide/copovidone were prepared by solvent evaporation and hot melt extrusion, and sized by mortar and pestle or cryomilling techniques, modulating the level of mechanical activation experienced by the sample. Drug loading (DL) of the binary ASD was varied from 5-50%, and ternary systems were formulated at 30% DL with two surfactants (sodium dodecyl sulfate, Vitamin E TPGS). Imaging of partially dissolved or crystallized compacts by scanning electron microscopy with energy-dispersive X-ray analysis and confocal fluorescence microscopy was performed to investigate pathways of hydration, phase separation, and crystallization. Monitoring drug and polymer release of ASD powder under non-sink conditions provided insight into supersaturation and desupersaturation profiles. Systems at the greatest risk of matrix crystallization had high DLs, underwent mechanical activation, and/or contained surfactant. Systems having greatest resistance to matrix crystallization had rapid and congruent drug and polymer release. This study has implications for formulation and process design of ASDs and risk assessment of matrix crystallization.

Improving Dissolution Performance and Drug Loading of Amorphous Dispersions Through a Hierarchical Particle Approach.

Co-precipitation is an emerging manufacturing strategy for amorphous solid dispersions (ASDs). Herein, the interplay between processing conditions, surface composition, and release performance was evaluated using grazoprevir and hypromellose acetate succinate as the model drug and polymer, respectively. Co-precipitated amorphous dispersion (cPAD) particles were produced in the presence and absence of an additional polymer that was either dissolved or dispersed in the anti-solvent. This additional polymer in the anti-solvent was deposited on the surfaces of the cPAD particles during isolation and drying to create hierarchical particles, which we define here as a core ASD particle with an additional water soluble component that is coating the particle surfaces. The resultant hierarchical particles were characterized using X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, and X-ray photoelectron spectroscopy (XPS). Release performance was evaluated using a two-stage dissolution test. XPS analysis revealed a trend whereby cPAD particles with a lower surface drug concentration showed improved release relative to particles with a higher surface drug concentration, for nominally similar drug loadings. This surface drug concentration could be impacted by whether the secondary polymer was dissolved in the anti-solvent or dispersed in the anti-solvent prior to isolating final dried hierarchical cPAD powders. Grazoprevir exposure in dogs was higher when the hierarchical cPAD was dosed, with ∼1.8 fold increase in AUC compared to the binary cPAD. These observations highlight the important interplay between processing conditions and ASD performance in the context of cPAD particles and illustrate a hierarchical particle design as a successful approach to alter ASD surface chemistry to improve dissolution performance.

Effect of drug load and lipid-wax blends on drug release and stability from spray-congealed microparticles.

This study was designed to evaluate paraffin wax as a potential controlled release matrix for spray congealing and its impact on drug release and stability of the microparticles. Paraffin wax can form a hydrophobic barrier to moisture and reduce drug degradation besides retarding drug release in the gastrointestinal tract. More hydrophilic lipid-based additives can be incorporated to modulate the drug release through the paraffin wax barrier. This study reports the findings of lipid-wax formulations at preserving the stability of moisture-sensitive drugs in spray-congealed microparticles. Aspirin-loaded microparticles formulated with different drug loads, lipid additives, and lipid:wax ratios were produced by spray congealing. Stearic acid (SA), cetyl alcohol (CA), and cetyl ester (CE) were the lipid additives studied. The microparticles were evaluated for yield, encapsulation efficiency, particle size, drug stability, and release. CE exhibited the greatest effect on increasing drug release, followed by CA and SA. Dissolution profiles showed the best fit to Weibull kinetic model. The degree of drug degradation was low, with CA imparting the least protective effect, followed by SA and CE. Paraffin wax is useful for preserving the stability of moisture-sensitive aspirin and retarding its release from spray-congealed microparticles. The addition of lipid additives modulated drug release without compromising drug stability.

Combining drug salt formation with amorphous solid dispersions - a double edged sword.

Glass transition temperature (Tg) is important for amorphous compounds because it can have implications on their physical and chemical stability. With drugs that possess ionizable acidic or basic groups, salt formation is a potential strategy to reduce re-crystallization tendency through Tg elevation. While salt formation has been reported to impact re-crystallization tendency, it is not known if this holds true for all drugs and if it is useful in the context of amorphous solid dispersion (ASD) formulations. In addition, little information on the impact of salt formation on drug release performance of ASD is available. Herein, the influence of salt formation and Tg elevation on the release performance of lumefantrine (Tg = 19.7 °C) when formulated as an ASD with copovidone (PVPVA) was examined. Lumefantrine salts and lumefantrine salt-PVPVA ASDs with drug loadings (DLs) ranging from 5 to 30% were prepared. The acids used for salt formation were benzoic acid, benzenesulfonic acid, camphorsulfonic acid, hydrochloric acid, p-toluenesulfonic acid, poly(ethylene) glycol 250 diacid (PEG 250 diacid), and sulfuric acid. Salt formation resulted in an elevation of Tg compared to lumefantrine free base, with the largest increase in Tg observed with lumefantrine sulfate. With a lower Tg salt, ASDs could be formulated at higher DLs while ensuring drug release. In contrast, drug release ceased at a DL as low as 5% when Tg of the salt was high. However, ASDs with lower Tgs such as the benzoate and PEG 250 diacid salts showed poor stability against re-crystallization when stored under stress storage conditions. When using a salt in an ASD formulation, attention should be paid to the Tg of the salt, since it may show opposing effects on physical stability and drug release, at least for PVPVA-based ASDs.

Balancing Solid-State Stability and Dissolution Performance of Lumefantrine Amorphous Solid Dispersions: The Role of Polymer Choice and Drug-Polymer Interactions.

Amorphous solid dispersions (ASDs) are of great interest due to their ability to enhance the delivery of poorly soluble drugs. Recent studies have shown that, in addition to acting as a crystallization inhibitor, the polymer in an ASD plays a role in controlling the rate of drug release, notably in congruently releasing formulations, where both the drug and polymer have similar normalized release rates. The aim of this study was to compare the solid-state stability and release performance of ASDs when formulated with neutral and enteric polymers. One neutral (polyvinylpyrrolidone-vinyl acetate copolymer, PVPVA) and four enteric polymers (hypromellose acetate succinate; hypromellose phthalate; cellulose acetate phthalate, CAP; methacrylic acid-methyl methacrylate copolymer, Eudragit L 100) were used to formulate binary ASDs with lumefantrine, a hydrophobic and weakly basic antimalarial drug. The normalized drug and polymer release rates of lumefantrine-PVPVA ASDs up to 35% drug loading (DL) were similar and rapid. No drug release from PVPVA systems was detected when the DL was increased to 40%. In contrast, ASDs formulated with enteric polymers showed a DL-dependent decrease in the release rates of both the drug and polymer, whereby release was slower than for PVPVA ASDs for DLs < 40% DL. Drug release from CAP and Eudragit L 100 systems was the slowest and drug amorphous solubility was not achieved even at 5% DL. Although lumefantrine-PVPVA ASDs showed fast release, they also showed rapid drug crystallization under accelerated stability conditions, while the ASDs with enteric polymers showed much greater resistance to crystallization. This study highlights the importance of polymer selection in the formulation of ASDs, where a balance between physical stability and dissolution release must be achieved.

Amorphous Solid Dispersions Containing Residual Crystallinity: Competition Between Dissolution and Matrix Crystallization.

Crystallinity in an amorphous solid dispersion (ASD) may negatively impact dissolution performance by causing lost solubility advantage and/or seeding crystal growth leading to desupersaturation. The goal of the study was to evaluate underlying dissolution and crystallization mechanisms resulting from residual crystallinity contained within bicalutamide (BCL)/polyvinylpyrrolidone vinyl acetate copolymer (PVPVA) ASDs produced by hot melt extrusion (HME). In-line Raman spectroscopy, polarized light microscopy, and scanning electron microscopy were used to characterize crystallization kinetics and mechanisms. The fully amorphous ASD (0% crystallinity) did not dissolve completely, and underwent crystallization to the metastable polymorph (form 2), initiating in the amorphous matrix at the interface of the amorphous solid with water. Under non-sink conditions, higher extents of supersaturation were achieved because dissolution initially proceeded unhindered prior to nucleation. ASDs containing residual crystallinity had markedly reduced supersaturation. Solid-mediated crystallization (matrix crystallization) consumed the amorphous solid, growing the stable polymorph (form 1). Under sink conditions, both the fully amorphous ASD and crystalline physical mixture achieve faster release than the ASDs containing residual crystallinity. In the latter systems, matrix crystallization leads to highly agglomerated crystals with high relative surface area. Solution-mediated crystallization was not a significant driver of concentration loss, due to slow crystal growth from solution in the presence of PVPVA. The high risk stemming from residual crystallinity in BCL/PVPVA ASDs stems from (1) fast matrix crystallization propagating from crystal seeds, and (2) growth of the stable crystal form. This study has implications for dissolution performance outcomes of ASDs containing residual crystallinity.

Insights into the Moisture Scavenging Properties of Different Types of Starch in Tablets Containing a Moisture-Sensitive Drug.

Starch is a commonly used excipient in the pharmaceutical industry. However, information on the effect of the moisture scavenging properties of starch to protect moisture-sensitive drugs is limited. The interaction between starch and moisture is of particular interest as moisture fugacity can impact drug stability. In this study, the moisture behavior of different starches was examined for an understanding of its role in the degradation of acetylsalicylic acid. The starches were characterized for their dimensional- and moisture-related properties. Stability testing was carried out on tablets containing acetylsalicylic acid and different starches. Although moisture sorption processes were visually comparable for the different starches, quantitative differences were found in their moisture interaction and distribution. From the sorption isotherms, moisture monolayer coverage and area of hysteresis were found to correlate well with the percentage of acetylsalicylic acid degradation. The lowest percentage of acetylsalicylic acid degradation was observed in starch that exhibited high monolayer coverage, large area of hysteresis, and good capacity for internally absorbed moisture. Findings from this study highlighted the value of moisture scavenging excipients when formulating moisture-sensitive drug products. Clearly, the assessment of moisture sorption properties of excipients during the preformulation phase can be an invaluable exercise for identifying the best possible ingredients in formulations where moisture sensitivity is an area of concern.

A mechanistic understanding of compression damage to the dissolubility of coated pellets in tablets.

Damage to the drug diffusion coat barrier of controlled release pellets by the compaction force when preparing multiple-unit pellet system tablets is a major concern. Previous studies have shown that pellets located at the tablet axial and radial peripheral surfaces were more susceptible to damage when compacted due to the considerable shear encountered at these locations. Hence, this study was designed to assess with precision the impact of pellet spatial position in the compact on the extent of coat damage by the compaction force via a single pellet in minitablet (SPIM) system. Microcrystalline cellulose (MCC) pellet cores were consecutively coated with a drug layer followed by a sustained release layer. Chlorpheniramine maleate was the model drug used. Using a compaction simulator, the coated pellets were compacted singly into 3 mm diameter SPIMs with MCC as the filler. SPIMs with individual pellets placed in seven positions were prepared. The uncompacted and compacted coated pellets, as SPIMs, were subjected to drug release testing. The dissolution results showed that pellets placed at the top-radial position were the most susceptible to coat damage by the compaction force, while pellets positioned within the minitablet at the middle and upper quadrant positions showed the least damage. The SPIM system was found to be effective at defining the extent of coat damage to the pellet spatial position in the compact. This study confirmed that coated pellets located at the periphery were more susceptible to damage by compaction, with pellets located at the top-radial position showing the greatest extent of coat damage. However, if the pellet was completely encrusted by the cushioning filler, coat damage could be mitigated. Further investigations were directed at how the extent of coat damage impacted drug release. Interestingly, small punctures were found to be most detrimental to drug release whilst coats with large surface cuts did not completely fail. A damaged pellet coat has some self-sealing ability and failure is not total. Thus, this study provides a deeper understanding of the consequence of coat damage to drug release when sustained release coated pellets are breached.

Understanding the release performance of pellets with hydrophobic inclusions in sustained-release coating.

The aim of this study was to evaluate how the addition of hydrophobic inclusions to sustained-release pellet film coat can affect drug release. Sustained-release formulations, in particular multiparticulate systems are gaining popularity because they are able to reduce the dosing frequency of drugs that require multiple dosing. In addition, the risk of dose dumping is low and local gastrointestinal irritation is minimised. Metformin-loaded pellets, prepared via extrusion-spheronisation, were coated with ethyl cellulose (EC)-based film coat, with and without hydrophobic inclusions to a series of coat thickness. Stearic acid 50 (SA) and hydrogenated castor oil (HCO) were the hydrophobic inclusions used. Drug release was investigated using the USP dissolution apparatus 2 and an ultraviolet imager. Release kinetics were analysed using the zero-order model. The physical properties of the pellets were characterised before and after dissolution. The addition of hydrophobic inclusions to EC-based film coat slowed down drug release, with SA slowing down drug release more than HCO. The influence of hydrophobic inclusions on drug release was clearly observable when the pellets were coated to 10% weight gain. It was postulated that the hydrophobic inclusions acted as physical barriers to increase the tortuosity of the diffusional path through the pellet film coat. The use of hydrophobic inclusions to control the rate of drug dissolution was shown to be promising. This could translate into potential cost and time savings with less materials and time used.

A study of the impact of excipient shielding on initial drug release using UV imaging.

Knowledge on the dissolution behaviour of a drug is critical for efficient and effective product development. As the drug has almost always to be formulated with excipients in the design of a dosage form, it is important to examine the implications of the choice of excipients on the dissolution of the drug, among others, especially in the case of an immediate release dosage form. The objective of this study was to explore the potential of using an ultraviolet (UV) imaging technique to examine the effect of drug-excipient ratio on the initial dissolution of the drug, when formulated with a hydrophilic, water insoluble excipient. A series of drug-excipient binary blends with different ratios were prepared and compacted into 2 mm compacts, and their dissolution profiles captured with a UV imager. Chemical imaging via Raman spectroscopy was also performed on the compacts to quantify the fraction of drug presented on the compact surface. At low drug concentrations, a suppression in drug dissolution was observed, but beyond a critical drug-excipient ratio, the concentration of the excipient no longer played a role in affecting drug dissolution rates. Drug particle size was found to affect the critical drug-excipient ratio required to negate the shielding effect exerted by the excipient, such that a higher proportion of drug was required. It is postulated that the excipient served as a physical barrier, as well as competitor for water required for wetting during initial dissolution, thereby causing a delay in the wetting and dissolution of the drug.

A Study of Moisture Sorption and Dielectric Processes of Starch and Sodium Starch Glycolate : Theme: Formulation and Manufacturing of Solid Dosage Forms Guest Editors: Tony Zhou and Tonglei Li.

PURPOSE: This study explored the potential of combining the use of moisture sorption isotherms and dielectric relaxation profiles of starch and sodium starch glycolate (SSG) to probe the location of moisture in dried and hydrated samples. METHODS: Starch and SSG samples, dried and hydrated, were prepared. For hydrated samples, their moisture contents were determined. The samples were probed by dielectric spectroscopy using a frequency band of 0.1 Hz to 1 MHz to investigate their moisture-related relaxation profiles. The moisture sorption and desorption isotherms of starch and SSG were generated using a vapor sorption analyzer, and modeled using the Guggenheim-Anderson-de Boer equation. RESULTS: A clear high frequency relaxation process was detected in both dried and hydrated starches, while for dried starch, an additional slower low frequency process was also detected. The high frequency relaxation processes in hydrated and dried starches were assigned to the coupled starch-hydrated water relaxation. The low frequency relaxation in dried starch was attributed to the local chain motions of the starch backbone. No relaxation process associated with water was detected in both hydrated and dried SSG within the frequency and temperature range used in this study. The moisture sorption isotherms of SSG suggest the presence of high energy free water, which could have masked the relaxation process of the bound water during dielectric measurements. CONCLUSION: The combined study of moisture sorption isotherms and dielectric spectroscopy was shown to be beneficial and complementary in probing the effects of moisture on the relaxation processes of starch and SSG.

Effect of moisture sorption on the performance of crospovidone.

Crospovidone is a commonly used tablet disintegrant. However, the synthetic disintegrant has been known to be hygroscopic and high moisture content in crospovidone used could exert deleterious effects on tablets formulated with it. The objective of this study was to elicit a better understanding between crospovidone-water interaction and its effect on disintegrant performance. Moisture sorption and desorption isotherms were obtained together with the enthalpy of immersion. Crospovidone samples stored at four relative humidities were used to formulate tablets and the resultant tablets were evaluated for their mechanical, dimensional and disintegratability attributes. Analyses of the moisture sorption isotherms indicated that externally adsorbed moisture accounted for the bulk of the total moisture content in crospovidone, with minimal amount of moisture absorbed intramolecularly. Enthalpy of immersion became less exothermic with crospovidone samples stored at increasing storage humidity. Correspondingly, improvement in disintegration time became less pronounced. This was postulated to be a consequence of premature wetting of the particle surfaces by externally adsorbed moisture. High humidity was also detrimental to tablet hardness and thickness. In conclusion, the impact of moisture sorption during storage by excipients such as crospovidone could be better understood by the appreciation of crospovidone-water interaction and its consequence on tablet quality.