Developments in Small-Volume Dissolution for Low-Dose Pharmaceuticals and Combination Devices

Dissolution is typically performed in US Pharmacopeia (USP) Apparatus 1 or 2 at 500 mL to 900 mL. Lower volumes may be needed due to low doses that cannot be analytically quantified in these volumes or in order to better mimic in vivo conditions.

For low-dose drugs, an adequate concentration of the drug is needed to properly analyze the sample at the first time point. The limit of quantitation must be lower than the expected release at the first time point to properly characterize the drug’s performance. Before moving to smaller volumes, regulatory agencies may request a demonstration that more sensitive analysis techniques, such as liquid chromatography-mass spectrometry, have been evaluated.

Smaller volumes can also be more relevant for modeling the in vivo environment. More medicines are being made for pediatric and pet populations, which have smaller volumes in their GI tract. Other formulations may be specifically designed to deliver to a single area of the body, driving the need for a lower volume. Some formulations are designed to dissolve and be absorbed in the mouth (eg, buccal and sublingual delivery). Drug-device implants are also increasingly used to deliver the drug load at a specific point in the body, such as via a drug-eluting stent or an eye implant. In these situations, it may not be biorelevant to use normal volumes.

What Are the Small-Volume Dissolution Options?

Multiple options are available for small-volume dissolution. Looking at the USP Apparatuses, the most common choices are:

• USP Apparatus 1 and 2: 100-mL, 200-mL, and 250-mL minivessels (Image 1)
• USP Apparatus 3: standard 300-mL vessels or 100-mL noncompendial vessels
• USP Apparatus 4: closed-loop configuration
• USP Apparatus 7: 50-mL, 100-mL, and 300-mL traditional vessels or 5-mL and 10-mL cells with the Agilent 400-DS System (Image 2)

Image 1

Close-up of a 400-DS USP Apparatus 7 10-mL cell with stent holder. This system has low volume and almost no evaporation, making it an excellent option for long-term-release products.

Image 2

A 200-mL minivessel and minipaddle setup shown in an Agilent 708-DS Dissolution Apparatus. The 708-DS can be modified to use 100-mL, 200-mL, and 250-mL small-volume kits along with the standard 1-L and 2-L volumes.

Of the above, USP Apparatuses 3, 4, and 7 offer lower volumes in a compendial system. The USP Apparatus 1 and 2 system minivessels are widely used but not compendial, with the exception of the 250-mL vessels in the Chinese Pharmacopoeia.

What Are the Challenges of Using Lower Volumes?

Small-volume-system users must ensure that the dissolution method is meaningful, robust, and discriminatory. Smaller volumes introduce additional challenges with media accuracy, hydrodynamics, and sampling. It is essential when choosing a system not to sacrifice the quality of the dissolution method.

Volume accuracy should be considered for the initial filling of the vessels, as should sampling intervals, media replacement, and evaporation. Pump accuracy is critical for maintaining volume, ensuring a reproducible dissolution environment and accurate calculations. Evaporation control is critical as well, especially for extended-release formulations and implants, as small evaporative losses can have outsized effects.

Proper mixing in smaller vessels must also be ensured. Like traditional systems, a moderate agitation speed should be chosen that balances robustness and discrimination. Sampling may also be more challenging, as the vessel diameters are typically smaller than those used for larger volumes.

How Have Low-Dose Implants Been Used?

The most challenging small-volume dissolution situations involve a variety of long-acting drugs that are implanted or injected into, including via drug-eluting stents, eye implants, and suspensions.1-3 These dosage forms share a release profile that spans several days or weeks and is intended for local delivery and absorption. These products tend to be very low dose, often with micrograms or nanograms of API. To achieve proper quantitation of the release, it is necessary to minimize dissolution volumes as much as possible.

The combination of low volume and long timeframes for release requires a system with little to no evaporation. Historically, many labs have chosen to place their implants in a sealed vial that is placed in a controlled temperature environment with some form of agitation. A rocking device placed in an incubator chamber and a rotating bottle apparatus are common options in this space. While these options meet the needs of low volume and evaporation, they are not USP compendial systems, cannot be automated, and offer unreliable agitation.

Among low-volume USP Apparatus 7 solutions, the Agilent 400-DS has been developed to specifically meet the needs of these dosage forms. This system can be used with either 5-mL or 10-mL cells and is sealed except during media handling. Agitation is achieved through a reciprocating holder inside the cell, which is moved by a magnetic drive positioned outside of the cell. Media handling and sampling is handled automatically, including the ability to change between different media as the run progresses. This system has been successfully used for a wide variety of formulation types, including accelerated dissolution studies. For implantable devices, accelerated dissolution can provide dissolution data in days rather than the weeks or months of release seen in vivo.

Intravaginal rings are among the earliest and most common implant types, often designed to release API for a year or longer, making traditional analytical methods difficult. A study comparing the release rate of intravaginal rings under typical in vivo conditions versus accelerated conditions using higher temperatures and stronger solvents (isopropyl alcohol, ethanol, and acetonitrile) found 1- and 2-fold reductions in testing time without sacrificing the discriminatory power of the dissolution method.4

What Is the “Take-Home?”

The push for lower-dose solid oral dosage forms and implants has required dissolution science to adapt along with it. A variety of compendial and noncompendial options are available to address the needs of these dosage forms. When choosing a small-volume apparatus, it is essential that the integrity of the dissolution itself must be maintained. Reproducible hydrodynamics and appropriate solvent choices are key to developing a method that will be predictive of in vivo release, discriminatory, and robust.

References

1. Seidlitz A, Schick W, Reske T, et al. In vitro study of sirolimus release from a drug-eluting stent: comparison of the release profiles obtained using different test setups. Eur J Pharm Biopharm. 2015;93:328-338.
2. Stein S, Auel T, Kempin W, et al. Influence of the test method on in vitro drug release from intravitreal model implants containing dexamethasone or fluorescein sodium in poly (d,l-lactide-co-glycolide) or polycaprolactone. Eur J Pharm Biopharm. 2017;127:270-278.
3. Probst M, Schmidt M, Tietz K, et al. In vitro dissolution testing of parenteral aqueous solutions and oily suspensions of paracetamol and prednisolone. Int J Pharm. 2017;532(1):519-527.
4. Externbrink A, Eggenreich K, Eder S, et al. Development and evaluation of accelerated drug release testing methods for a matrix-type intravaginal ring. Eur J Pharm Biopharm. 2017;110:1-12.