Elucidating the effect of crystallization on drug release from amorphous solid dispersions in soluble and insoluble carriers

Ojo, Andrew Toye; Ma, Congshan; Lee, Ping I.

doi:10.1016/j.ijpharm.2020.120005

Cited by 22 publications

(13 citation statements)

References 30 publications

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“…In this case, the seed crystals act as a nucleation site to accelerate crystal growth under the conditions studied. During dissolution, this translates to a lower maximum achieved concentration of the ASD with increasing levels of crystallinity for water-soluble polymers ( Moseson et al, 2020 ; Ojo et al, 2020 ). This is important because it is not always possible to eliminate residual crystallinity when processing ASDs.…”

Section: Introductionmentioning

confidence: 99%

“…In their study, the impact on the dissolution of equivalent amounts of unprocessed crystalline material showed a greater rate and extent of drug release in all cases compared to an equivalent amount of crystallinity that endogenously crystallized during storage (i.e., the amorphous drug recrystallizing due to instability) ( Theil et al, 2018 ). Similarly, Ojo et al utilized accelerated temperature and humidity conditions to grow controlled amounts of crystallinity (i.e., 5% and 10% crystallinity) in ASDs formulated using a water-soluble polymer (i.e., PVP K12) and a water-insoluble polymer (i.e., HPMCAS) ( Ojo et al, 2020 ). The authors purposely preferred endogenously grown crystals because seed crystals potentially cloud the effects on intrinsic dissolution from the dissimilar nature of endogenously formed and spiked crystallinity.…”

Section: Introductionmentioning

confidence: 99%

“…However, in insoluble polymers, the crystals are trapped in the insoluble matrix, which restricts crystal growth to drug diffusion through the matrix. This limits crystal growth and ultimately limits desupersaturation in solution ( Ojo et al, 2020 ). These studies highlight the fact that the presence of crystallinity not only affects dissolution, but changes in the crystalline surface area or surface energy can also negatively affect the dissolution profile and cannot be modeled by spiking with unprocessed crystalline drug ( Moseson et al, 2020 ; Ojo et al, 2020 ; Que.…”

Section: Introductionmentioning

confidence: 99%

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Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

Davis

Miller²,

Santitewagun

et al. 2021

International Journal of Pharmaceutics: X

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We seek to further addresss the questions posed by Moseson et al. regarding whether any residual crystal level, size, or characteristic is acceptable in an amorphous solid dispersion (ASD) such that its stability, enhanced dissolution, and increased bioavailability are not compromised. To address this highly relevant question, we study an interesting heat- and shear-labile drug in development, LY3009120. To study the effects of residual crystallinity and degradation in ASDs, we prepared three compositionally identical formulations (57–1, 59–4, and 59–5) using the KinetiSol process under various processing conditions to obtain samples with various levels of crystallinity (2.3%, 0.9%, and 0.1%, respectively) and degradation products (0.74%, 1.97%, and 3.12%, respectively). Samples with less than 1% crystallinity were placed on stability, and we observed no measurable change in the drug's crystallinity, dissolution profile or purity in the 59–4 and 59–5 formulations over four months of storage under closed conditions at 25 °C and 60% humidity. For formulations 57–1, 59–4, and 59–5, bioavailability studies in rats reveal a 44-fold, 55-fold, and 62-fold increase in mean AUC, respectively, compared to the physical mixture. This suggests that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

Davis

Miller²,

Santitewagun

et al. 2021

International Journal of Pharmaceutics: X

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“…Polymers are important excipients for improving API solubility and preventing the recrystallization of APIs in ASDs. − The mixing of APIs and polymers at the molecular level will increase the glass transition of amorphous API/polymer formulations, which could probably improve the stability of formulations during storage . Law et al studied the physical stability of amorphous ritonavir-poly(ethylene glycol) 8000 (PEG 8000) formulations under the conditions of 25 °C and 57.5% relative humidity (RH) and found that PEG 8000 maintained the amorphous state of ritonavir for 10 months.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic Mechanism of Physical Stability of Amorphous Pharmaceutical Formulations

Qiao

2023

Ind. Eng. Chem. Res.

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Hygroscopicity is an important factor affecting the physical stability of amorphous solid dispersions (ASDs) during long-term storage. In this work, the effects of temperature, relative humidity (RH), and polymeric excipients on the phase behavior of amorphous irbesartan (IRB) and oxaprozin (OXA) were systematically investigated. The ASDs were prepared by the solvent evaporation method. The water sorption in formulations was measured under the conditions of 25 °C, 60% RH, 25 °C, 90% RH, and 40 °C, 75% RH. The results showed that the hygroscopicity of formulations containing polyvinylpyrrolidone (PVP) was stronger than that containing poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA 46) and the hygroscopicity increased with increasing temperature and RH. With increasing content of active pharmaceutical ingredients (APIs), the recrystallization phenomenon is significant at the same RH. PVP can better inhibit IRB recrystallization than PVPVA 46. In contrast, PVPVA 46 can better maintain the amorphous form of OXA than PVP. The thermodynamic phase diagrams of amorphous API/polymer formulations at 60% RH and anhydrous conditions were predicted using perturbed chain statistical associated fluid theory (PC-SAFT) and the Gordon−Taylor equation. Furthermore, the electrostatic potential (ESP) and binding energies between APIs and polymers were calculated with density functional theory (DFT), which explained the molecular interaction mechanism of ASDs. This work is expected to guide the screening of excipients and API loadings for designing ASDs and the selection of storage conditions.

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“…ASDs have been widely used in formulating poorly soluble drugs, and currently, more than 30 commercially available medicines are formulated using the ASD technology. , For these oral dosage forms, dissolution is the prerequisite for satisfactory absorption in the gastrointestinal tract. , However, the dissolution mechanism of ASDs remains elusive, and the dissolution performance depends on many factors related to formulation design and dissolution conditions. Once in contact with dissolution media, the hydrated ASDs may undergo drug crystallization or amorphous–amorphous phase separation while the drug and polymer are dissolving. , At the same time, drug crystallization or liquid–liquid phase separation may also occur spontaneously in the dissolution media that is often time supersaturated . All these potential events make the dissolution behavior very complex and unpredictable.…”

Section: Introductionmentioning

confidence: 99%

Water-Resistant Drug–Polymer Interaction Contributes to the Formation of Nano-Species during the Dissolution of Felodipine Amorphous Solid Dispersions

et al. 2022

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Drug–polymer interactions are of great importance in amorphous solid dispersion (ASD) formulation for both dissolution performance and physical stability considerations. In this work, three felodipine ASD systems with drug loading ranging from 5 to 20% were prepared using PVP, PVP-VA, or HPMC-AS as the polymer matrix. The amorphization and homogeneity were confirmed by differential scanning calorimetry and powder X-ray diffraction. The intrinsic dissolution behavior of these ASDs was studied in 0.05 M HCl and phosphate-buffered saline (PBS) (pH 6.5). In 0.05 M HCl, PVP-VA ASDs with low drug loading (<15%) showed rapid dissolution accompanied with nano-species generation, while in the PVP system, rapid dissolution and nano-species generation were observed only when drug loading was less than 10%, and HPMC-AS ASDs always released slowly with no nano-species formation. In PBS, PVP-VA ASDs with drug loading less than 10% showed rapid dissolution accompanied with nano-species generation, while for PVP ASDs, rapid dissolution and nano-species generation were observed only when drug loading was 5%. However, 20% drug loading HPMC-AS ASDs exhibited rapid dissolution of felodipine and nano-species generation. When the drug loading was above the transition point of PVP-VA ASDs and PVP ASDs, the release rate was significantly lowered, and no nano-species was generated. To understand this phenomenon, drug–polymer interactions were studied using the melting point depression method and the Flory–Huggins model fitting. The Flory–Huggins interaction parameters (χ) for felodipine/HPMC-AS, felodipine/PVP, and felodipine/PVP-VA were determined to be 0.62 ± 0.07, −0.55 ± 0.20, and −1.02 ± 0.21, respectively, indicating the existence of the strongest attractive molecular interaction between felodipine and PVP-VA, followed by felodipine/PVP, but not in felodipine/HPMC-AS. Furthermore, dynamic vapor sorption further revealed that the molecular interactions between felodipine and PVP or PVP-VA were resistant to water. We concluded that water-resistant drug–polymer interactions in felodipine/polymer systems were responsible for the formation of nano-species, which further facilitated the rapid initial drug dissolution.

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Elucidating the effect of crystallization on drug release from amorphous solid dispersions in soluble and insoluble carriers

Cited by 22 publications

References 30 publications

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

Thermodynamic Mechanism of Physical Stability of Amorphous Pharmaceutical Formulations

Water-Resistant Drug–Polymer Interaction Contributes to the Formation of Nano-Species during the Dissolution of Felodipine Amorphous Solid Dispersions

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