METHODSFour model weak bases (erlotinib, gefitinib, ketoconazole, and dipyridamole) were tested as received. Gastric transfer tests were performed by adding fasted state simulated gastric fluid (FaSSGF, 0.1 N HCl, pH 2) to the model drug and then transferring to fasted state simulated intestinal fluid (FaSSIF, pH 6.5 PBS with 0.22% SIF powder) by addition of a concentrated FaSSIF solution. Drug in capsules were tested at 50 mL to 100 mL volume in a 100 mL USP 2 apparatus.

Precipitation inhibition as a function of concentration and HPMC concentration was carried out using the Pion µDiss ProfilerTM. Drug and polymer were mixed in pH 2 FaSSGF until fully dissolved and then a concetrated FaSSIF was added to reach a final pH 6.5 and 0.22% SIF (FaSSIF).

All dissolution data was acquired using UV fiber optic probes.

RESULTSErlotinib, gefitinib, ketoconazole, and dipyridamole all readily dissolve in gastric fluid (FaSSGF) and precipitate on transfer to intestinal buffer (FaSSIF). In this work, we characterize the precipitation of these model compounds as a function of dose and concentration of HPMC. In the presence of HPMC, precipitation can be delayed minutes up to greater than two hours depending on the drug and dose. At a concentration between the amorphous solubility and half the amorphous solubility, the in vitro area under the curve (AUC) for 90 minutes in FaSSIF is about two times higher in the presence of 0.2 mg/mL HPMC for all four compounds. Only a minor delay in precipitation occurs in the presence of gelatin.

Increasing the concentration of HPMC above 0.1 mg/mL has only a minor effect on precipitation while increasing the concentration significantly increases the precipitation rate in the presence or absence of HPMC.

Capsule Selection Guidance: Bioequivalence or Enhancement of Vcaps® Plus Relative to Gelatin Capsules Based on Drug Properties

T3167

Michael Grass, Ian Yates, Alex Lineweaver, Mike Morgen (Capsugel Pharmaceutical R&D Bend OR)

PURPOSEVcaps® Plus, made from hydroxypropyl methylcellulose (HPMC), are an attractive alternative to gelatin capsules. They are plant-based, have improved crack resistance at low humidity, and are rapidly dissolving.a

Several studies have demonstrated that capsule composition can affect the bioavailability of drugs due to either disintegration rate or interactions between the drug and the capsule materials.b,c

One type of interaction is inhibition or delay of precipitation for supersaturating formulations in the presence of certain polymers, such as HPMC. Weakly basic drugs can have much higher solubility in low pH gastric fluid than in intestinal fluids and therefore lead to supersaturation upon transfer from gastric to intestinal fluid. The precipitation rate of these drugs in intestinal fluids can impact bioavailability and therefore the impact of capsule material must be understood during development.

CONCLUSIONS

HPMC-based capsules such as Vcaps® Plus can be used to inhibit precipitation of weak base actives on transfer from gastric to intestinal buffer. The observed enhancement can be understood primarily from the dose and amorphous solubility of the drug and secondarily by the interaction between the drug and HPMC.

ACKNOWLEDGEMENTSWe wish to acknowledge Dr. Keith Hutchison for his support.

REFERENCES a. D. Cadé. Vcaps® Plus Capsules – Hypromellose Capsules for Pharmaceutical Products (http://www.capsugel.com/ihc/vcaps-plus)b. D.B. Warren, et al. “Using polymeric precipiation inhibitors to improve the absorption of poorly water-soluble drugs: A mechanistic basis for utility.” J. Drug Targeting, 18 (10), 704 – 731 (2010)c. Ouellet et al. “Effect of Particle Size, Food, and Capsule Shell Composition on the Oral Bioavailability of Dabrafenib, a BRAF Inhibitor, in Patients with BRAF Mutation-Positive Tumors.” J. Pharm. Sci. 102 (9), 3100 – 3109 (2013)d. Y. Chen et al. “Drug-Polymer-Water Interaction and its Implication for the Dissolution Performance of Amorphous Solid Dispersions.” Mol. Pharmaceutics, 12 (2), 576 – 589 (2015)

Effect of drug concentration on the precipitation of erlotinib

Model Drug PropertiesProperty Erlotinib Gefitinib Ketoconazole Dipyridamole

MW 393 447 531 505pKa 5.4 5.3, 7.0 6.2 6.4logP 3.0 4.1 4.3 3.9

Xtal Sol (pH 2) µg/mL

420 (HCl) or 1200 (FB) > 3000 > 4000 > 5000

Xtal Sol (FaSSIF) µg/mL 7.6 116 14 19

Am. Sol (FaSSIF)µg/mL 170 740 490 265

Dose 150 mg q.d. (fasted) 250 mg q.d. 200 mg q.d. 100 mg

Structure

Dissolution of model compounds in FaSSGFfollowed by transfer to FaSSIF dosed as powder in capsule (PIC) in either gelatin or Vcaps® Plus.

Vcaps® Plus

Gelatin

Gelatin

Vcaps® Plus

Vcaps® Plus

GelatinVcaps® Plus

Gelatin

Dependence of Supersaturation Parameter d on Dose

0

0.2

0.4

0.6

0.8

1

1.2

0 10 20 30 40 50

Supe

rsat

urat

ion

Para

met

er (S

P)

Dose/Solubility (xtal)

Gefitinib

Erlotinib

Ketoconazole

Dipyridamole

𝑆𝑆𝑆𝑆 =𝐴𝐴1

𝐴𝐴1 + 𝐴𝐴2

Effect of HPMC concentration on the precipitation of erlotinib

USP II Dissolution of API in gelatin or Vcaps® Plus capsules. HPMC provides sustainment of a supersaturated state for weak bases.

With Pre-dissolved HPMC No Polymer

The addition of at least 0.1 mg/mL HPMC has a large effect on the precipitation rate of erlotinib at 100 µg/mL. Additional polymer addition increases the lag time with no effect on precipitation rate.

Erlotinib is a rapid crystallizer in the absence of polymer at > 25 µg/mL. The addition of 0.1 mg/mL HPMC delays precipitation over a range of concentration.

A plot of supersaturation parameter (SP) vs. supersaturation ratio (SR) demonstrates the utility of a polymeric precipitation inhibitor (PPI) for each compound. The utility rank orders compound according to their amorphous solubility enhancement:

Ketoconazole (35) > Erlotinib (22) = Dipyridamole (> 14) > Gefitinib (6.4)

Larger Polym

er Effect