FORMULATION DEVELOPMENT – Impact of Excipients & Manufacturing Process on Solubility-Enhanced Ritonavir Tablet Size & Weight Reduction
Drug formulators and pharmaceutical manufacturers continue to experience and navigate low aqueous solubility challenges. With the human body made up of approximately 65% water, oral drugs must have certain water-solubility levels to fully dissolve into the bloodstream.1 At the same time, low aqueous solubility limits new drugs’ oral bioavailability and commercial viability significantly. In fact, studies suggest that 40% of drugs fail to reach pharmacy shelves due to this very issue.2 Furthermore, drugs equipped with poor water solubility traits can present negative clinical effects and increased risks for patients.
Poor solubility typically results from stable crystalline forms that cannot fully absorb into fluids. Chemical and physical drug modification methods are evolving to optimize drug solubility and dissolution. For example, amorphous solid dispersions (ASDs) are a favored technique to increase solubility and bioavailability. ASDs can be used in a polymeric carrier to stabilize the active pharmaceutical ingredient (API) and bolster its solubility. This combination actively protects APIs against precipitation or re-crystallization upon contact with intestinal fluids.
As drug manufacturers battle with low solubility challenges, research has found that specific excipients – such as disintegrants and bulking agents − notably improve the biopharmaceutical performance of dosage forms. In this study, IFF researchers investigate bulking agents and disintegrants to develop efficacious Rotonavir tablets with improved in vitro release.
PROCESS OF PRODUCTION
Formulators are exploring and discovering new production processes for drugs with low solubility. Hot melt extrusion (HME) is a leading technology to produce ASDs. HME is a relatively straightforward, solvent-free process that transforms a powder blend of crystalline APIs and polymers into an extrudate for optimal solubilization. HME works by disrupting the crystal lattice of the API to promote its transition into an amorphous form. This unique, continuous manufacturing process is well-known for producing polymer products with a consistent shape and density. The API’s amorphous properties allow for successful incorporation into the polymeric carrier for a homogenous dispersion. Homogenous dispersion refers to the finely dispersed API particles or solid API solution in a polymer, resulting from HME’s thermal and mechanical energy.3
HME is commercially successful; however, the number of acceptable polymers suitable for the process is limited.4 Hydroxypropyl methylcellulose (HPMC) is a favored water-soluble polymer for solid dispersion formation. HPMCs can help prevent API crystallization and maintain stable solid dispersions, promoting effective drug disintegration.5-7
Solid dispersions is a key technology for developing solid oral dosage forms containing APIs with bioavailability challenges. As such, researchers used a proprietary polymer tailored to address API’s solubilization performance requirements. AFFINISOLTM HPMC HME 15 LV − an excipient specially designed for HME – can generate highly soluble ASDs from poorly soluble compounds within a broad processing window. Compared to marketed HPMCs, this excipient has a significantly lower glass transition temperature and melt viscosity, making it ideal for thermal processability.8-10
HPMCs act as binders in conventional tablets; however, they also promote gelling polymer network (GPN) formation. The GPN initiates a slower API release, hindering rapid tablet disintegration. Additional disintegrants or bulking agents may be required to maintain tablet performance.10-12
EXCIPIENTS & TABLET MASS FOR SOLUBILITY ENHANCEMENT
While solubility enhancement is critical, it is not enough to generate an efficacious drug product. Optimal downstream processing and tablet mass are essential considerations. Tablet mass plays a major role in the compressibility, hardness, friability, disintegration time, and release of the API. If overlooked, these elements can limit solubility-enhanced actives from converting into a tablet dosage form.
A polymer’s content can range from 50%-90% of the ASD, directly influencing tablet weight and size.10-12 Irrespective of ASD bulking agents and disintegrants play a dominant role in tableting and disintegration when evaluated in vitro or in vivo.
Tablet mass can determine esophageal transit ease and timing, regardless of patient factors or administration technique (patient position, use of fluids, etc). In this respect, smaller tablets have generally displayed faster transit times among patients.
Researchers attempted to formulate a smaller Ritonavir tablet with improved bioavailability through HME. The effects of formulating with different bulking agents and disintegrant concentrations were investigated.
Ritonavir is a poorly soluble drug used for HIV-infection treatment.13 Previous studies have confirmed that when Ritonavir is formulated into an ASD, the drug’s solubility and commercial viability can significantly improve. However, Ritonavir exhibits thermal instability above its melt temperature, which presents challenges for the HME process.
To promote process temperature reduction, additional excipients may be required to ensure stability of each component through HME. With that said, drug manufacturers should be cautious as additives can create undesired formulation complexity. Close collaboration with a reliable supplier partner – equipped with formulation and process expertise – is recommended.
Researchers used a mixture with a 1:2 ratio of Ritonavir and HPMC, based on previous screening trials. The API and polymer were blended for 10 minutes. The blend was then passed through a 30# mesh sieve and fed through a Thermo Fisher Pharma 11 twin-screw extruder at 120°C to obtain extrudates.
The extrudates were cut into pellets (1-2 mm) using a Varicut Pelletizer, and further milled using a Retsch Ultra-Centrifugal Mill ZM 200 to achieve extrudates with a particle size of < 250 μm. The milled extrudates were blended with various bulking agents (Avicel® PH 102 or Directly Compressible Anhydrous Lactose) and tablet disintegrants (Ac-Di-Sol® SD-711).
The various blends were then compressed on an 8 Station Kambert tablet compression machine (KMP-D-8) using standard concave 12-mm round punches. Upon the tablets’ completion, they were evaluated for hardness, disintegration time, and in vitro drug release.
RESULTS & DISCUSSION
Applied compression force can significantly influence tablet hardness and disintegration timing. While a stronger compression force increases the chance of a GPN forming, a compression force that is too low results in physically weak tablets with increased friability, which can be a major limiting factor for manufacturers.11,12
The application of correct excipients can help optimize tablet properties, eg, tablet weight and drug release. Bulking agents or fillers are utilized as spacers among ASD particles to prevent a GPN from forming. For example, microcrystalline cellulose (MCC), an insoluble filler, is widely used in DC.
MCC can increase tablet strength and decrease porosity after atmospheric moisture exposure. Avicel® PH 102 − a purified, partially depolymerized alphacellulose excipient – is obtained by the acid hydrolysis of specialty wood pulp. This MCC is most often used in tableting as a compression aid, flow aid, and filler for directly compressed tablets.
Researchers developed round-shaped Ritonavir tablets with 12-mm diameters and thickness varying from 5.6 mm to 6 mm, based on composition and weight. The performance of MCC and Anhydrous Lactose (AL) was then evaluated as water-insoluble and water-soluble fillers, respectively.
The drug release from tablets formulated with bulking agents – MCC or AL – was not complete as the tablets disintegrated after 20 minutes. The tablets’ initial water uptake indicated immediate GPN formation. GPNs can hinder rapid tablet disintegration; therefore, additional disintegrants were needed to achieve a faster disintegration time.13,14
In the case of AL, atmospheric water was absorbed by the hygroscopic amorphous lactose fraction. There was an initial increase in tablet hardness, but water content negatively impacted AL’s glass transition temperature (Tg). At a critical value, AL’s Tg dropped below ambient temperature. When this transaction occurs, the amorphous material morphs into a crystalline state. Crystallization occurring at the surface of AL promotes GPN formation, which further hinders tablet disintegration.
MCC can undergo plastic deformation at a relatively low yield pressure, which helps prepare dense compacts at low compression forces.15,16 By incorporating this filler, researchers saw a significant increase in tablet hardness, compared to those formulated with AL.
As observed in Figure 1, MCC yielded stronger tablets. This formulation was further evaluated to study the effects of varying disintegrant concentrations (Ac-Di-Sol® SD-711 from 2%-4% w/w).
Researchers also observed the impact of Ac-Di-Sol® – an internally cross-linked sodium carboxymethyl cellulose (NaCMC) that aids in tablet disintegration and dissolution – on tablet disintegration time.
Results showed that increasing the concentration of NaCMC enhanced tablet disintegration time. Therefore, the rate and extent of liquid uptake and water penetration into the tablets was improved. Disintegrant particles in such powder mixtures likely make up a continuous network or skeleton, which helps facilitate plastic deformation and disintegration processes.16,17
NaCMC has consistent disintegrative functionality due to its efficient water uptake and rapid swelling properties. Exposure to water causes this excipient to swell and exert pressure against surrounding tablet ingredients. The increased swelling prompts existing bonds between particles to break. The tablet’s quick disintegration time exposes drug particles to the dissolution medium, resulting in rapid drug release.16,17
The formulation with 4% NaCMC showed a faster and complete drug release, compared to the control and 2% NaCMC.
As a final test, researchers developed a round-shaped in-house formulation with MCC and 4% NaCMC. As shown in Figure 4, this tablet provided a complete drug release within 15 minutes. The tablet weighed 525 mg – 20% lower than the marketed formulation (675 mg).
The smaller, round-shaped in-house tablet exhibited a faster disintegration rate compared to the marketed formulation. The results showed that tablets with 20% lower weight than typical marketed formulations deliver a superior in vitro dissolution performance.
These results present ample opportunities for drug manufacturers seeking to overcome low solubility challenges. Based on the in-house tablet’s release profile, excipients can heavily influence tablet mass for drug bioavailability, solubility, and patient compliance.
Formulation and process designs are both critical to consider when manufacturing efficacious tablets. By utilizing bulking agents and tablet disintegrants, researchers successfully developed a Ritonavir ASD tablet through HME with optimal physical and drug-release properties.
Excipients can significantly impact the bioavailability of dosage forms. The research team’s combination of a bulking agent and disintegrant (MCC and NaCMC) helped improve tablet strength and disintegration timing. These results suggest a bright future for the manufacturing and processing of previously unviable APIs. With the appropriate formulation methods, physical properties and excipients, improved drug performance, and commercial viability may be achieved.
While study results are promising, developers should remain cautious when looking to incorporate excipients for increased drug bioavailability. Regulatory standards and risk assessment protocols for new delivery methods continue to evolve. Close collaboration between drug manufacturers and reliable suppliers is recommended to not only improve formulations, design, and cost, but further propel the commercial availability of new, innovative pharmaceutical products.
- Kakran, Mitali et al. “Overcoming The Challenges Of Poor Drug Solubility”. Ispe.Gr.Jp, 2012, https://www.ispe.gr.jp/ISPE/02_katsudou/pdf/201304_en.pdf.
- Improving Solubility and Bioavailability of Poorly Water Soluble Drugs by Solid Dispersion Technique – A Review, International Journal of Pharmaceutical Sciences Review and Research, November-December 2013, http://globalresearchonline.net/journalcontents/v23- 1/42.pdf.
- Agrawal, A.M., Dudhedia, M.S. & Zimny, E. Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale. AAPS PharmSciTech 17, 133–147 (2016). https://doi.org/10.1208/s12249-015-0425-7
- Repka, Michael A., Soumyajit Majumdar, Sunil Kumar Battu, Ramesh Srirangam, and Sampada B. Upadhye. “Applications of hot-melt extrusion for drug delivery.” Expert opinion on drug delivery 5, no. 12 (2008): 1357-1376.
- Guo, Jian-Hwa, G. W. Skinner, W. W. Harcum, and P. E. Barnum. “Pharmaceutical applications of naturally occurring water-soluble polymers.” Pharmaceutical science & technology today 1, no. 6 (1998): 254-261.
- Huang, Siyuan, Kevin P. O’Donnell, Justin M. Keen, Mark A. Rickard, James W. McGinity, and Robert O. Williams. “A new extrudable form of hypromellose: AFFINISOL™ HPMC HME.” AAPS PharmSciTech 17, no. 1 (2016): 106-119.
- O’Donnell, K.P., Shrestha, U., Rickard, M., Keene, E., Vanchura, B., Mayfield, D. The Influence of Apparent Viscosity of AFFINISOL™ HPMC HME on Hot Melt Extrusion Processability and Drug Release from Amorphous Solid Dispersions. 2016
- Gayatri Khanvilkar, Ajit Bhagat, Tejas Gunjikar, Sangmesh Torne, Amina Faham. “Formulation Development – Formulating Immediate-Release Tablets for Poorly Soluble Drugs”. Drug Development & Delivery June 2020
- Huang, S., O’Donnell, K. P., de Vaux, S. M. D., O’Brien, J., Stutzman, J., & Williams III, R. O. (2017). Processing thermally labile drugs by hot-melt extrusion: The lesson with gliclazide. European Journal of Pharmaceutics and Biopharmaceutics, 119, 56-67.
- O’Donnell, K. P., & Woodward, W. H. (2015). Dielectric spectroscopy for the determination of the glass transition temperature of pharmaceutical solid dispersions. Drug development and industrial pharmacy, 41(6), 959-968.
- Desai, Parind Mahendrakumar, Celine Valeria Liew, and Paul Wan Sia Heng. “Review of disintegrants and the disintegration phenomena.” Journal of pharmaceutical sciences 105, no. 9 (2016): 2545-2555.
- Démuth, B., Nagy, Z. K., Balogh, A., Vigh, T., Marosi, G., Verreck, G.& Brewster, M. E. (2015). Downstream processing of polymer-based amorphous solid dispersions to generate tablet formulations. International journal of pharmaceutics, 486(1-2), 268-286.
- Ritu Kaushik, Kevin P. O’Donnell, Gopeshkumar Singh. “Impact of Extrusion Process Parameters on Drug Recovery and Dissolution Performance of Solid Dispersions of Ritonavir and AFFINISOL™ HPMC HME.” Dow Pharma & Food Solutions
- Pharmaceutical Technology EXCIPIENTS & SOLID DOSAGE FORMS 2004 – New Developments in Spray-Dried Lactose Gerad Bolhuis, Klaas Kussendrager, and John Langridge
- Vromans, H., Bolhuis, G. K., Lerk, C. F., & Kussendrager, K. D. (1987). Studies on tableting properties of lactose. VIII. The effect of variations in primary particle size, percentage of amorphous lactose and addition of a disintegrant on the disintegration of spray-dried lactose tablets. International journal of pharmaceutics, 39(3), 201-206.
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Gayatri Khanvilkar, as a Application and Innovation Specialist at IFF Pharma Solutions, has focused her career at the intersection of pharmaceutics, Good Laboratory Practice, JMP, R&D, and regulatory affairs. She earned her Master’s degree in Pharmacy with a focus in Pharmacology and her Bachelor’s degree in Pharmacy from Mumbai University.
Ajit Bhagat is a Senior Technologist at IFF Pharma Solutions, based in Hyderabad, India. He earned his Bachelor’s degree from Mumbai University and is well-trained in equipment operations and experimental design for formulation development.
Dr. Tejas Gunjikar is the pharma application and innovation leader at IFF Pharma Solutions, focused on oral fast-dissolving technologies, biopharmaceutical formulations, solid oral dosage forms, and more. He earned his PhD in Pharmaceutics from University of Mumbai, and his Bachelor’s degree in Pharmacy from Savitribai Phule Pune University.
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