Abstract
With as high as 60% of drugs in company pipelines exhibiting poor aqueous solubility, the ability to successfully develop a poorly water-soluble drug has become essential. Gaining a detailed understanding of a compound through preformulation studies can be especially challenging for poorly water-soluble drugs limiting their development. Therefore, this chapter focuses on the application of preformulation studies essential in understanding a poorly water-soluble drug, including solubility studies, solid-state characterization of the active ingredient and formulations thereof, and in vitro and in vivo testing of the lead formulations.
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Appendices
Method Capsule 1pH-Solubility Profile by Direct Determination in Aqueous Suspension
Based on the method reported by Li et al. (2005)
Objective
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To determine the pH-solubility profile of haloperidol and the corresponding hydrochloride and mesylate salts.
Equipment and Reagents
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Haloperidol free base
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Haloperidol hydrochloride
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Haloperidol mesylate
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Deionized water
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Hydrochloric acid solution
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Sodium hydroxide solution
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10 mL sealable vials
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Water bath or environmental shaker capable of maintaining 37°C
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0.45 μm acrodisc filters w/attached syringe
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UV spectrophotometer (250 nm detection wavelength)
Method
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Add 5 mL of water to each 10 mL vial, 9 total, 3 for each compound.
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Place excess solids (one compound per vial) in the prefilled vials such that a suspension results.
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Titrated each vial to pH 1 via HCl and NaOH solution addition.
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Equilibrate the vials at 37°C for 24 h. Note: agitation recommended during equilibration if possible.
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Following equilibration, verify that no pH shift has occurred.
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Remove an aliquot of the suspension and filter through a 0.45 μm (or smaller) filter.
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Dilute sample with suitable organic solvent (i.e., acetonitrile) to obtain concentrations in the working linear range of the spectrophotometer.
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Analyze samples on UV spectrophotometer at 250 nm.
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Titrate each vial with NaOH and HCl solutions to pH 2.
-
Equilibrate vials for 24 h under identical conditions.
-
Confirm no pH shift upon equilibration.
-
Repeat sampling and analysis procedure as above.
-
Continue titration, equilibration, sampling procedure through pH range of 1–13, or desired regions thereof.
Results
-
Plotting the solubility (ug/mL) versus pH of the free base and its HCl salt revealed a significant drop in solubility of both compounds above pH 5. Additionally, the plot demonstrates no significant difference in the aqueous solubility between the free base and HCl salt through pH 7.
-
The pH versus solubility plot for the mesylate salt of haloperidol revealed significantly higher solubilities of the API through pH 5. Similar to the free base and HCl salt, solubility of the API decreased significantly above pH 5.
Method Capsule 2Analysis of Drug–Excipient Interactions Via Differential Scanning Calorimetry
Based on the method reported by Mura et al. (1998a) Thermochimica Acta.
Objective
-
To determine compatibility of picotamide in the presence of excipients commonly used in tableting formulations.
Equipment and Reagents
-
Picotamide recrystallized from water–ethanol 8:1.
-
Excipients: PVP K30, PVPXL, tartaric acid, ascorbic acid, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, Veegum F, Arabic gum, cornstarch.
-
Mortar pestle
-
Microbalance (mg scale)
-
Differential scanning calorimeter
-
Aluminum pans with perforated lits
Method
-
Sieve each material and obtain the 75–150 μm fraction for analysis.
-
Prepare individual physical mixtures the API and each excipient (1:1) in a mortar using a spatula to gently blend the components.
-
Prepare co-ground mixtures of each drug:excipient combination by grinding an aliquot of the corresponding physical mixture in a mortar with a pestle for 10 min.
-
Prepare kneaded mixtures of each drug:excipient combination by slurring an aliquot of the corresponding physical mixture with ethanol (1–2 mL) and grinding in a mortar with pestle to obtain a paste. Dry under vacuum in a desiccator at room temperature to a constant weight.
-
Place aliquots of physical mixtures at 60°C for drug–excipient storage stability analysis.
-
Analyze each individual component, physical mixture, co-ground mixture, kneaded mixture, and stability sample in the following manner: Place an aluminum pan (without lid) on the microbalance and zero the scale. Fill the pan with approximately 5–10 mg of the material for analysis. Place the filled pan back on the balance and record the exact weight of filling. Place a lid in the filled pan. Place the pan in the DSC apparatus on the sample side. A reference pan with lid should be placed on the reference cell. Perform scan at 10 K/min from 30–200°C.
Results
-
Picotamide monohydrate exhibits an endothermic event at 123.0  ±  2.4°C.
-
Maintenance of the anhydrous state for physical mixtures and co-ground mixtures with microcrystalline cellulose, cornstarch, methocel, and ethocel indicate compatibility.
-
Hydration of the API in physical mixtures with Veegum and Arabic gum indicates incompatibility.
-
Fresh and stored physical blends with PVP exhibited no interactions. The presence of the dehydration peak at 124°C for ground mixtures with PVP-XL indicates incompatibility. The absence of the picotamide melting endotherm for co-ground mixtures with PVP-K30 indicates amorphization of the API and dissolution into the polymeric carrier.
-
The presence of acidic excipients yielded broadening and downshift of thermal effects followed by exothermic decomposition for all samples indicating strong incompatibility.
Method Capsule 3X-Ray Diffraction Parameter Optimization
Based on the method reported by Tiwari et al. (2007)
Objective
-
To optimize the scan parameters for X-ray diffraction analysis including step size and dwell time as well as to assess the influence of particle size.
Equipment and Reagents
-
Olanzapine polymorphs I and II
-
X-ray diffractometer
-
Poly methyl methacrylate sample holder or equivalent
-
Glass microscope slide or similar
Method
-
Pass polymorph I through multiple sieves (i.e., BSS #80, 120, and 240) collecting aliquots of each sieve fraction.
-
Optimization of scan rate–scan a 5% w/w mixture of polymorph I in polymorph II over the range of 3–40° 2Q under the following conditions and identify the parameters capable of providing the greatest number of identified peaks in the least amount of time:
-
Step time of 0.5 s, step size of 0.025°
-
Step time of 0.5 s, step size of 0.0125°
-
Step time of 1 s, step size of 0.0125°
-
Step time of 5 s, step size of 0.05°
-
Step time of 5 s, step size of 0.0125°
-
Using the selected optimized scan rate, analyze the aliquots of each sieve fraction to assess the influence of particle size.
Results
-
A step time of 5 s and step sizes of 0.05 and 0.0125° allowed identification of four distinct peaks.
-
Lower step times of 1 s and 0.5 s allowed identification of only two and one peaks, respectively, regardless of step size.
-
The step size of 0.05° was selected as it drastically reduced the scan time from 246.66 min to 61.66 min.
-
Particle size significantly influenced the number of identifiable peaks.
-
Sieve fraction BSS #120/240 significantly improved resolution compared to larger particle-size fractions.
Method Capsule 4Accelerated Stability Monitoring of Amorphous Solid Dispersions
Based on the method reported by DiNunzio et al. (2010a, b, c)
Objective
-
To assess formulation stability against recrystallization upon storage for amorphous itraconazole compositions produced by hot–melt extrusion and Kinetisol dispersing.
Equipment and Reagents
-
High-density polyethylene (HDPE) bottles or similar with induction sealing capability.
-
Oven capable of maintaining 40°C  ±  1°C.
-
Saturated salt solution capable of maintaining 75% relative humidity within 40°C oven.
-
X-ray diffractometer (XRD)
-
Sample holder for XRD
Method
-
Analyze bulk itraconazole and excipients individually by XRD over the scan range of 5–50° 2Θ with a step size of 0.05° and a dwell time of 3 s. Identify major characteristic peaks to be used in subsequent analysis.
-
Analyze physical mixtures of drug and excipients at ratios identical to those used for the final formulation by XRD employing the same parameters as above. Identify the major characteristic peaks of itraconazole present in physical mixtures.
-
Following formulation production, immediately obtain XRD profiles for each product using identical scan parameters as before. Identify major characteristic peaks of itraconazole and corresponding intensities if present.
-
Place 2 g of a single formulation into a 30-mL HDPE bottle.
-
Prepare three bottles for each formulation for each of the three time points.
-
Induction seal each bottle.
-
Verify induction seal robustness prior to placing on stability.
-
Place all samples in 40°C 75% RH oven.
-
At 1 month remove three samples of each formulation for analysis.
-
Allow samples to equilibrate to room temperature for 24 h.
-
Open containers and analyze powders individually by XRD using identical parameters as described above for characteristic crystalline peaks of itraconazole.
-
Repeat sample removal, equilibration, and analysis at 3 and 6 months.
-
Generate a plot for the XRD data of intensity versus angle (degrees 2Θ) for all formulations at a single time point for comparison. Do this for each time point.
Results
-
Analysis of bulk itraconazole revealed numerous characteristic crystalline peaks between 10 and 35° 2Θ.
-
XRD diffraction patterns of formulations immediately post production exhibit amorphous halos and lack any characteristic itraconazole peaks.
-
Materials produced by kinetisol dispersing which contained no plasticizer exhibited no peak growth over time when stored at accelerated conditions.
-
Formulations produced by hot–melt extrusion exhibited gradual growth of characteristic itraconazole peaks, indicating recrystallization upon storage.
Method Capsule 5BET Specific Surface Area Determination for a High Surface-Area Heat-Liable Material
Based on the method reported by Engstrom et al. (2007)
Objective
-
To determine the specific surface area of protein powders produced by spray freezing into liquid.
Equipment and Reagents
-
Protein powder produced by spray freezing into liquid.
-
Quantachrome Nova 2000 BET apparatus including sample cells.
-
Dry box
-
Liquid nitrogen
-
Nitrogen gas: high purity, dry
-
Analytical balance
Method
-
Using the analytical balance, weigh the empty sample cells and record the weights.
-
Within the dry box, add powder sample to the BET sample cells. As the device has two cells which can be analyzed simultaneously, all powders for analysis are to be analyzed in duplicate.
-
Using the analytical balance record the weight of the full sample cell.
-
Attach filled sample cells to degassing station ports.
-
Engage vacuum
-
Allow samples to degas under vacuum for 12 h.
-
Fill liquid nitrogen Dewar with liquid nitrogen to the maximum fill level.
-
Repressurize the system, remove sample cells, and, using the analytical balance, immediately record the weights of the degassed samples. Calculate sample weight as: Degassed sample cell weight–empty sample cell weight.
-
Attach sample cells to analysis ports of the BET apparatus. Verify the level of liquid nitrogen in the Dewar is sufficient for analysis.
-
Using nitrogen as the adsorptive gas analyze the powder samples over the relative pressure range of 0.05–0.30 and use the BET equation to fit the adsorption data.
Results
-
Surface areas of powders produced by spray freezing into liquid ranged from 13 to 134 m2/g.
-
Increasing the feed concentration decreased the specific surface area of the powders.
-
Increasing the feed concentration decreased the submicron particle content.
-
Increasing the droplet size during spray freeze drying resulted in lower specific surface areas.
Method Capsule 6Supersaturation Dissolution Studies Using the Syringe/Filter and Microcentrifuge Methods
Based on the method reported by Curatolo et al. 2009
Objective
-
To determine the ability of HPMCAS in initiation and maintenance of supersaturation of an experimental compound.
Equipment and Reagents
-
Experimental compound CMPD 2
-
HPMCAS-MF
-
10-mL syringes
-
Model fasted duodenal fluid preheated to 37°C.
-
Oven capable of maintaining 37°C.
-
Wheel capable of rotating syringe in horizontal position at 50 rpm.
-
20-gauge hypodermic needles
-
13 mm, 0.45 μm polyvinylidine diflouride syringe filters.
-
Test tubes
-
Polypropylene microcentrifuge tubes
-
Microcentrifuge
-
Vortex mixer
-
Small volume pipette (i.e., 10–100 μL)
-
Diluting solution: 60:40 1.7 wt.% ammonium ascorbate:acetonitrile.
-
HPLC: Phenomenex ultracarb ODS 20 analytical column, PDA detection at 215 nm.
Method
-
Syringe/Filter method:
-
Accurately weigh 7.5 mg of 67% CMPD 2:HPMCAS-MF formulation and add to an empty 10 mL syringe with attached 20-gage needle.
-
Draw 10 mL of model fasted duodenal fluid preheated to 37°C into the syringe via the attached needle.
-
Replace attached needle with 13 mm syringe filter.
-
Shake syringe vigorously for 30 s.
-
Expel six drops of the solution as waste. Collect drops 7–19 as a sample.
-
Draw syringe plunger back to generate an air bubble.
-
Place syringe on rotating wheel (50 rpm) in the 37°C oven.
-
Dilute sample 1:1 with diluting solvent.
-
Repeat sampling procedure at t  =  5, 10, 20, 40, 90, 180 min.
-
Analyze samples on HPLC to quantify CMPD 2.
-
Microcentrifuge method
-
In a 37°C controlled-temperature box, weigh 1.8 mg of formulation into a microcentrifuge tube.
-
Add 1.8 mL of model fasted duodenal fluid to the tube.
-
Close tube, start timer, and vortex mix for 60 s.
-
Transfer tube to microcentrifuge, allow to stand for 6 min, then centrifuge at 13,000  g for 60 s.
-
At the 10 min mark on the timer, remove a 25-μL sample from the supernatant via a pipette. Immediately dilute 1:1 with diluting solution.
-
Resuspend the material via vortex mixing for 30 s.
-
Place tube back in centrifuge. Allow tube to stand undisturbed until the next sampling time point.
-
At each sampling time point, centrifuge the tube for 60 s, remove supernatant sample and resuspend as described. Dilute sample 1:1 with diluting solution.
-
Analyze all samples via HPLC to quantify CMPD 2.
-
Plot the dissolved drug concentration versus time dissolution profile for the API.
Results
-
Compound 2 has an aqueous solubility of 1 μg/mL.
-
The 67% compound 2 solid dispersion formulation with HPMCAS resulted in supersaturation of the test medium.
-
Maximum concentrations of approximately 130 μg/mL were achieved.
-
HPMCAS-MF initiated and maintained supersaturation of compound 2 to a greater extent than HPC, PVAP or the crystalline bulk drug.
-
Both methods proved successful in achieving supersaturation
Method Capsule 7Biphasic Dissolution Testing Utilizing an External Flow through Cell
Based on the method reported by Shi et al. (2010)
Objective
-
To examine the dissolution profiles of three celecoxib formulations using a biphasic dissolution-testing method incorporating an organic phase for drug partitioning.
Equipment and Reagents
-
Octanol
-
Sodium phosphate monobasic monohydrate
-
Sodium hydroxide
-
Gelatin capsules
-
Commercial Celebrex capsules (200 mg dose strength).
-
Extracted celecoxib (extracted from Celebrex capsules via ethanol and subsequent evaporation method).
-
USP Dissolution Apparatus II
-
USP IV flow through cell
-
Piston pump
-
Teflon tubing
-
Modified apparatus II paddle incorporating a second paddle capable of agitating the organic layer during dissolution testing.
-
HPLC (mobile phase 55:45 v/v acetonitrile:ammonium acetate solution).
Method
-
Place 250 mL of 80 mM phosphate buffer (pH 6.8) in the dissolution vessel.
-
Add 200 mL of octanol to the dissolution vessel.
-
Prior to beginning the study, saturate the aqueous phase with octanol and vice versa by agitating the mixture for 30 min.
-
Allow all media to equilibrate to 37°C  ±  0.2°C.
-
Place the Teflon tubing (inlet and outlet) such that the ends are well within the aqueous phase of the dissolution media.
-
Set the paddle speed to 75 rpm.
-
Place the formulation for analysis into the flow through cell.
-
Set the pump flow rate to 30 mL/min.
-
At time points of 15, 30, 45, 60, 75, 90, and 120 min remove a 1-mL sample from the aqueous phase and a 100-μL sample from the organic phase. Do not replace the media.
-
Immediately centrifuge the aqueous phase samples at 14,000 rpm for 6 min. Collect the supernatant for HPLC analysis.
-
Immediately dilute the organic phase samples 100-fold with HPLC mobile phase.
-
Quantitative celecoxib via HPLC analysis; adjustment for dilution mathematically.
Results
-
Corresponding single-phase studies (aqueous; USP Apparatus II) under sink conditions were not discriminatory for formulation performance.
-
Nonsink two-phase dissolution revealed the same formulation performance rank order in the aqueous phase.
-
Analysis of the octanol phase reveals the self-emulsifying drug delivery Âsystem (SEDDS) outperformed the solution and capsule formulations.
-
SEDDS provided a higher amount of free drug compared to the solution Âformulation in which the drug was associated as surfactant micelles.
-
SEDDS formulation supersaturated the aqueous media under nonsink-biphasic dissolution conditions, allowing greater partitioning into the octanol phase.
-
Aqueous phase AUC values from both single and biphasic dissolution testing exhibited no correlation with in vivo AUC values.
-
Analysis of the octanol phase from biphasic studies revealed a rank-order Âcorrelation to in vivo results.
Method Capsule 8Supersaturation Dissolution Testing of Amorphous Compositions of a Poorly Water-Soluble Drug
Based on the method reported by DiNunzio et al. 2008
Objective
-
To assess the supersaturation extent and duration of amorphous compositions of itraconazole using concentration enhancing polymers.
Equipment and Reagents
-
Itraconazole; bulk drug and formulations prepared via thin film freezing.
-
Commercial itraconazole capsules (Sporanox).
-
Size 9 porcine gelatin capsules.
-
USP Dissolution Apparatus II with autosampler.
-
0.1N hydrochloric acid.
-
0.2M Na3PO4 solution.
-
0.2 μm PTFE membrane, 13 mm Acrodisc syringe filters.
-
5 mL syringes
-
HPLC System (5 μm°C18(2) 100  Å, 150 mm  ×  4.6 mm column, flow rate of 1 mL/min, detection at 263 nm).
-
HPLC mobile phase (70:30:0.05 acetonitrile:water:diethanolamine).
-
HPLC vials.
-
Vortex mixer
Method
-
Preheat 735 mL of 0.1N HCl in each dissolution vessel to 37°C.
-
Accurately weigh an amount of formulation equivalent to 37.5 mg of itraconazole. This corresponds to approximately 10Ă— the equilibrium solubility in 0.1N HCl.
-
Pre-wet the weighed powder with 15 mL of heated 0.1N HCl (37°C).
-
Add the prewetted powder slurry to the dissolution vessel.
-
After 2 h, add 250 mL of 0.2 M Na3PO4 to each vessel to bring the pH to 6.8.
-
At time points of 60, 120, 130, 150, 180, 240, 300, 360, and 1,440 min, a 5 mL sample is to be taken via the autosampler without replacement of the withdrawn media.
-
Immediately filter samples following withdraw through a 0.2-μm PTFE membrane.
-
Immediately dilute filtrate 1:1 with mobile phase and vortex mix. Transfer to an HPLC vial.
-
Analyze all samples by HPLC to quantify itraconazole adjusting for the volume change and dilution mathematically.
Results
-
Sporanox pellets were able to rapidly and extensively supersaturate the acidic media. Following the pH transition, the drug rapidly precipitated.
-
Thin film freezing formulations resulted in significantly reduced acidic media concentrations as the polymers used were enteric.
-
Following pH change, cellulose acetate phthalate and polyvinyl acetate phthalate formulations showed the greatest supersaturation in neutral media.
-
Higher ratios of itraconazole:polymer yielded lower degrees of supersaturation.
-
Cellulose acetate phthalate formulations provided longer half-life values for drug in solution, indicating strong concentration enhancing properties.
Method Capsule 9Pulmonary Delivery to the Murine Model Via Dry Powder Insufflation
Based on the method reported by Morello et al. (2009)
Objective
-
To achieve successful pulmonary administration of the tuberculosis vaccine (BCG) to the murine model by dry powder insufflation.
Equipment and Reagents
-
Female BALB/c mice (6–12 weeks old, 18–24 g).
-
BCG vaccine spray-dried powder.
-
Polyethylene tubing (1.19 mm diameter) cut into lengths of approximately 1 cm.
-
Microbalance
-
Penn-Century dry powder insufflator model DP-4 M.
-
Penn-Century model AP-1 air pump.
-
Rodent work stand
-
Lidocaine applicator
-
Mouse-sized speculum
-
Plastic incisor loop
-
Otoscope set
-
Ketamine HCl, xylazine, and acepromazine
-
Yohimbine solution (0.04 mg/mL)
-
Syringe and 21-gauge needle
-
Cage maintained at 37°C.
Method
-
Prepare mixture of ketamine/xylazine/acepromazine by mixing 2 mL ketamine at 100 mg/mL, 0.4 mL of xylazine at 100 mg/mL and 0.6 mL of acepromazine at 10 mg/mL with 7 mL of sterile phosphate–buffered saline.
-
Anesthetize the mouse via an intraperitonial (i.p.) injection (100 μL/20 g body weight) of ketamine/xylazine/acepromazine mixture
-
Load 200–300 μg of powder into the 1 cm segment of polyethylene tubing by dipping the end vertically into the powder bed 4–6 times.
-
Place the filled polyethylene tube into the hole within the insufflator chamber.
-
Attach base of insufflator to the cannula.
-
Place the mouse in the supine position on the mouse work station and place the incisor loop and lateral supports in position.
-
Raise the stand to 60°.
-
Using the otoscope, obtain a clear view of the trachea.
-
Using the speculum to guide the applicator, apply lidocaine to the arytenoid cartilage.
-
Re-obtain visual focus of the trachea with the otoscope.
-
Insert the cannula of the insufflator device into the tracheal opening.
-
Remove the otoscope and attach the air pump.
-
Depress plunger on air pump 4–5 times. Monitor rise and fall the upper chest as confirmation of proper insufflation.
-
Remove mouse from the work stand and give an i.p. injection of 0.11 mg/kg yohimbine solution (0.04 mg/mL)
-
Provide 300 μL 0.9% saline subcutaneously to aid recovery.
-
Move mouse to a 37°C cage until awake.
Results
-
Application of this method allowed rapid administration of the compound relative to similar methods.
-
≥90% of loaded powder was delivered to the lungs.
-
91% of the loaded dose reached the lungs.
-
Minor pulmonary damage occurred as a result of the procedure; however, mice were asymptomatic and congestion/hemorrhage resolved over time.
-
The method developed can be modified for use with larger animals by adjusting the dose and air volumes employed.
Method Capsule 10 Oral Drug Delivery of a Poorly Water-Soluble Drug to the Rat Model
Based on the method reported by Wempe et al. 2007
Objective
-
To determine the bioavailability of letrozole complexed with hydroxybutenyl-β-cyclodextrin (HBenβCD) compared to that of the native API via an oral dose administered as a suspension or solution to the rat model.
Equipment and Reagents
-
Letrozole, complexed to HBenβCD and unprocessed.
-
Male and female Sprague–Dawley rats (260–294 and 218–262 g, respectively).
-
1-mL syringe with 0.01-mL graduations.
-
Sterile glass vials
-
Ethanol
-
Sterile water
-
Sonicator
-
Oral gavage needle (16 gage).
-
Mini-capillary tubes containing EDTA di-potassium salt.
Method
-
Weigh 5.2 mg of letrozole (uncomplexed) into a sterile glass vial.
-
Immediately before dosing, dilute with 12.5% ethanol in water to a concentration of 1 mg/mL using sonication to disperse.
-
Weigh 626.2 mg complexed letrozole-HBenβCD into a glass vial.
-
Immediately before dosing, dilute with 12.5% ethanol in water to generate a 1 mg/mL solution.
-
With the gavage needle attached to the syringe, draw in the desired dose of the suspension or solution to be administered.
-
Holding the rat vertically while supporting the hind legs against the body, insert the gavage needle extending it into the stomach and expel the dose. Immediately remove the gavage needle from the animal.
-
Repeat dosing for all rats.
-
At time points of 0.45, 1.5, 2, 2.6, 2.9, 3.6, 5.1, 6.2, 8.3, 13.9, 24.8, and 36.3 h, collect 125 μL blood samples through the tail vein directly into mini-capillary tubes containing EDTA di-potassium salt.
-
Immediately following blood sample collection, cap the tube and place on dry ice. Keep samples frozen at −80°C until sample preparation for analysis.
Results
-
Letrozole was eliminated from the blood of male rats within 36 h following dosing via oral gavage.
-
The pharmacokinetics of letrozole are strongly gender-dependent.
-
Dosing of letrozole-HBenβCD yielded a twofold increase in the AUC compared to a suspension of the uncomplexed drug.
-
Oral dosing of the complexed formulation increased the Cmax from 87 to 140 ng/mL.
-
The T max was decreased from 8.4 h to 6.3 h by the HBenβCD formulation.
-
Solubility limits the rate and extent of absorption in male rats while only Âlimiting the rate of absorption in female rats.
-
Complexation of letrozole with HBenβCD improved oral absorption in male rats while maximizing absorption in female rats
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© 2012 American Association of Pharmaceutical Scientists
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O’Donnell, K.P., Williams, R.O. (2012). Optimizing the Formulation of Poorly Water-Soluble Drugs. In: Williams III, R., Watts, A., Miller, D. (eds) Formulating Poorly Water Soluble Drugs. AAPS Advances in the Pharmaceutical Sciences Series, vol 3. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1144-4_2
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DOI: https://doi.org/10.1007/978-1-4614-1144-4_2
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