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I.  Introduction

Drug Dissolution Testing

Drug dissolution testing is routinely used to provide critical in vitro drug release information for quality control purposes to assess batch-to-batch and drug development consistency and to predict in vivo drug release profiles1. In vitro drug dissolution data generated from dissolution testing can be related to in vivo pharmacokinetic data through in vitro-in vivo correlations (IVIVC).

To ensure consistent quality and predict in-vivo performance, the US-FDA mandates pharmaceutical companies to develop an in vitro drug exchange (IVDE) method capable of distinguishing changes in drug composition and achieving release profiles.

The dissolution testing method development for emerging special dosage forms is quite challenging. The quality of the dosage forms, other than clear solutions, can be effectively evaluated using in vitro exchange methods. The selection of apparatus is more challenging for special dosage forms due to the nature of the drug products. Apparatus 4: Flow through cell has utility for a number of dosage form types, for example, stents, implants, nano and microparticles, and liquid filled capsules2. Similarly, Apparatus 4 use can be explored for lipophilic (oil based) drug matrix.

Parenteral Lipophilic Drug Matrices

Dissolution testing conducted in the USP Apparatus 4 can be used to develop such an exchange method for long-acting parenteral lipophilic drugs (Figure 1). Parenteral lipophilic drug matrices are used to maintain high drug concentrations in the blood for prolonged duration. These products are meant to release a drug over a long period of time. Enhanced physical stability of a drug resulting in fewer injections has been shown to improve patient compliance. Therefore, it is critical to establish a rigorous dissolution test to achieve consistent quality and similar in-vivo performance.

art 2 fig 1

We have developed an IVDE method capable of discriminating critical changes in the drug product composition and achieving time-dependent release profiles in a reasonable timeframe. The method employs USP Apparatus 4: Flow-through cell for in vitro exchange followed by high-pressure liquid chromatography-ultraviolet (HPLC-UV) quantification of percentage drug exchanged. The USP Apparatus 4 exchanges media during the flow-through using a special cell containing the drug product. The cell is maintained at a constant temperature, typically 37°C, via a water jacket. The unique design allows sampling and media changes without affecting the thermodynamics inside the flow-through cell where the drug exchange is taking place.

II. SGS IVDE Method Development Studies

Our IVDE method was developed over the course and completion of multiple studies. We vetted all proposed parameters, carefully selecting and testing the best hardware, media, and processes for the desired outcome of each drug dissolution testing step.

Solubility of API. The first phase of the project assessed the solubility of API in different modulated exchange media. The exchange media evaluated including aqueous media at different pH and aqueous media with surfactants, and organic media. Drug release in aqueous media was limited, so of the many media tested for solubility. Based on this study, following media selected for IVDE development: 0.06M polyoxyethylene 1-lauryl ether (POE), 10% Triton-X-100, and 40% isopropyl alcohol (IPA) in propylene glycol (PG) media (Table 1).

art 2 tab 1

Media Selection. 0.06M POE, 10% Triton-X-100, and 40%IPA in PG media were used to perform IVDE method. 400 µL sample was loaded on a semi-solid adapter (Sotax) and the adapter was closed using a semi-permeable membrane (Strat-M Membrane). The adapter was placed inverted, membrane facing down into 22.6 mm cell. The IVDE release was studies using different media and time-dependent profile were plotted. Only 40%IPA-PG media showed reasonable release. It was decided to use 40%IPA-PG media for further optimization studies (Figure 2).

art 2 fig 2

Membrane Selection. The membrane for the semi-sold adapter was chosen after performing percent drug exchange experiments. A dialysis membrane (3.5 to 5 kDa) was compared against the Strat-M membrane (Millipore). Due to time-dependent release obtained, the Strat-M membrane was chosen for further method development (Figure 3).

art 2 fig 3

Flow Rate. The flow rates were optimized on the USP Apparatus 4, tested at different percentage of drug exchange rates over time (hours) during the development of these criteria. Flow rates ranged from 4 mL/minute to 32 mL/minute. Eight mL/minute was selected as optimal for final conditions. The 2-hour time point was found to be critical for the method to be discriminatory, and the release at each 2-hour mark was flow-rate dependent (Figure 4).

art 2 fig 4

Discriminatory Ability. Regulatory agencies typically ask sponsors to support the discriminatory ability of the selected IVDE method. The IVDE method was evaluated to gauge its discriminatory capability using multiple formulated batches, varying in composition, and analyzing these batches to assess IVDE method’s discriminatory ability. Each IVDE profile was assessed using the similarity factor (f2) calculation (Table 2).

art 2 tab 2

The similarity factor (f2) is a logarithmic reciprocal square root transformation of the sum of squared errors, and is a measurement of the similarity in the percentage dissolution between the two curves,

f2 = 50 × log {[1+ (1/n)Σt=1n (Rt - Tt)2]-0.5 × 100}

Where n is the number of time points, Rt is the dissolution value of the reference batch at time t, and Tt is the dissolution value of the test batch at time t. The IVDE method discriminated key component changes in the formulation. The final method parameters selected are listed in Table 3.

art 2 tab 3 a

art 2 tab 3 b

Method precision. To demonstrate our IVDE method’s precision, using final chosen parameters we tested multiple batches of the final batch formulation. The percentage of the drug released over time was plotted in Figure 5. Comparable profiles were obtained for all three parenteral lipophilic drug batches. These data demonstrate our method is precise.

art 2 fig 5

III. Conclusions

The IVDE method we developed using USP Apparatus 4: Flow Through cell with semi-solid adapter is precise where more than 80% drug release is achieved in about 24 hours. The method is discriminatory to the key changes in the formulation and can be used to monitor product performance at release and on stability.

Due to the nature of the method, multiple time-points were chosen to capture release profile nature. The drug exchange rate was very high up through the 2 hour time point and subsequently plateaued after 4 hour time interval. The drug exchange was most discriminatory at 2 hour time point (based on similarity factor f2); and 2 hour time point was proposed as a part of the release specifications. The method will need to be validated for specificity/placebo interference, linearity/range, accuracy/recovery, precision, robustness, and standard and sample solution stability.

Consequently, a similar method development approach can be taken for other lipophilic drugs that are difficult to solubilize in aqueous media.

IV. References

1 Bai G, Wang Y, Armenante PM. Velocity profiles and shear strain rate variability in the USP Dissolution Testing Apparatus 2 at Different Impeller Agitation Speeds. International Journal of Pharmaceutics, 2011;403 (1-2):1-14.

2 Vivian Gray. Hot Topics in Dissolution Testing. American Pharmaceutical Review, April 2012, Volume 15Issue 3.

3 Bhardwaj U and Burgess DJ. A novel USP apparatus 4 based release testing method for dispersed systems. International Journal of Pharmaceutics. 30 March 2010;388(1-2):287-294.

4 Siewert M, Dressman J, Brown CK, and Shah VP. FIP/AAPS guidelines to dissolution/in vitro release testing of novel/special dosage forms. AAPS PharmSciTech. 2003;4(1):Article 7.


Sunil S Potdar
Formulation Development Manger
SGS Life Science Services (Chicago, IL, USA)

Sonja Soloway
Senior Analyst
SGS Life Science Services (Chicago, IL, USA)

Gayla Velez
Operations Manager
SGS Life Science Services (Chicago, IL, USA)