The following materials were procured: Melperone hydrochloride from Lundbeck (Padova, Italy); Sugar Spheres, NF (25–30 mesh, 45–60 mesh, or 60–80 mesh) from Paulaur Coporation (Cranbury, NJ); hydroxypropylcellulose NF (Klucel® LF) from Ashland Aqualon (Hopewell, VA); ethylcellulose, NF (Ethocel Standard 10 Premium) from Colorcon (West Point, PA); Hypromellose phthalate (HP-55) from Shin Etsu Chemical Company (Tokyo, Japan); triethyl citrate and dibutyl sebacate from Vertellus Performance Chemicals (Greensborro, NC); polyethylene glycol (PEG 400) from Dow Chemicals (Manro, LA), a plasticizer; Dibasic Sodium Phosphate Anhydrous from Jost Chemicals (St. Louis, MO); D-mannitol (Pearlitol 25) from Roquette (France); Crosspovidone, NF (Polyplasdone XL-10) from GAF (Wayne, NJ); Sucralose, NF from Tate & Lyle (Singapore, China); magnesium stearate from Tai Hei Chemical (Tokyo, Japan); Wintergreen and peppermint from Synergy (Wauconda, IL); Gelatin Capsules, NF from Capsugel® (Greenwood, SC).
Melperone exhibits non-linear pharmacokinetics particularly above 50
mg. Since the target dose strength of melperone for the treatment of psychosis in patients associated with PD is 50
mg, the PK data available for 25 and 50
(unpublished data, H. Larsson, Department of Biochemistry, AB Ferrosan, Malmo, Sweden 1976) were used to derive target release profiles for a sustained release formulation suitable for a once-daily dosing regimen (). These pharmacokinetic profiles were utilized to estimate the pharmacokinetic parameters using WinNonlin version 4.1 (Pharsight Corporation, Mountain View, CA). Despite the absence of a well defined distribution phase in the case of melperone as reported6
, the intravenous (IV) and oral data could be fitted well to a two compartment model described by the following equation:
Where C (ng/mL) is the concentration in the central compartment, Ka (hr−1) is the first order absorption constant, F is the bioavailability, D (ng) is the dose, V (mL) is the volume of distribution, K12 (hr−1) is the rate constant into the peripheral compartment, K21 (hr−1) is the rate constant from the peripheral compartment, α (hr−1) is the distribution rate constant, β (hr−1) is the elimination rate constant, T (hr) is time, and Tlag (hr) is the lag time.
The fitting and parameter estimates are shown in and . The predicted plasma profiles are very similar to the actual plasma concentration-time profiles following oral and IV administrations of melperone.
Determination of Cav,ss for melperone
Using the estimates of the plasma concentration, profiles for melperone were generated. AUC0-t,ss
was obtained from simulated data at steady state were τ
12 hours. The Cav,ss
was calculated using the following relationship:
Solubility of melperone as a function of pH
An excess of melperone HCl was suspended in 0.1N HCl, USP Water, or in a phosphate buffer at a pH of 4.5, 6.8, 7.0, 7.1, or 7.8 for about 30
min while stirring, and the filtered aliquot was diluted with HPLC mobile phase and the solubility was determined by HPLC (see for solubility values).
Solubility (mg/mL) of melperone HCl.
Melperone SR beads, CR capsules, ODT-CR
A schematic for the SR bead and corresponding CR capsules or ODT-CR tablet comprising such SR beads is shown in . For the preparation of CR capsules, melperone hydrochloride is layered onto 20–25 mesh sugar spheres producing IR beads at a drug load of 25% w/w and 2% w/w seal coat of Klucel®
LF (hydroxypropylcellulose). These IR beads are coated with water-insoluble ethylcellulose (Ethocel Standard 10 Premium) with polyethylene glycol (PEG 400) as the plasticizer, and filled into hard gelatin capsules (50
mg dose) on a capsule filler, MG-2 Futura as discussed in detail elsewhere8
. For preparing ODT-CR tablets, melperone hydrochloride is layered onto 60–80 mesh or 45–60 mesh sugar spheres producing IR beads at a drug load of 25% w/w and 2% w/w seal coat of Klucel LF (hydroxypropylcellulose). These IR beads are coated with an alkaline buffer coat comprising anhydrous dibasic sodium phosphate and further coated with water-insoluble ethylcellulose (Ethocel Standard 10 Premium) with dibutyl sebacate or triethyl citrate as the plasticizer to produce SR beads. The SR beads prepared by either of the processes described above are referred to as Diffucaps®
beads. These SR beads blended with rapidly dispersing microgranules (AdvaTab®
base granules), prepared as described in detail elsewhere9,10
, microcrystalline cellulose, sucralose, a flavor (peppermint or wintergreen) and compressed into ODT-CR tablets (50
mg dose weighing 1000
mg) on a rotary tablet press equipped with an external lubrication system (e.g., Hata Tablet Press- Matsui ExLub System) and 15
mm round, flat faced, radius edge tooling11
Schematic of SR bead (Diffucaps® bead comprising an inert core sequentially coated with a drug layer, a protective seal coat, an alkaline buffer layer, and an outer SR polymer coat).and CR Capsules and ODT tablet comprising SR beads.
Preparation of melperone IR beads
Melperone hydrochloride was slowly added to 50/50 acetone/water while stirring until dissolved. A Glatt GPCG 5 equipped with a 9” bottom spray Wurster 13” column, 25
mm partition gap, 14
mm tubing, bottom air distribution ‘D’ plate with 200 mesh screen, atomization air pressure of 1.30 bar and 1.0
mm nozzle diameter was charged with 3000
g of sugar spheres (e.g. 20–25 mesh, 25–30 mesh, 45–60 mesh, or 60–80 mesh; for incorporation into ODT formulations, the starting sugar spheres need to be as small as possible to avoid grittiness, while for filling into capsules the starting sugar sphere size is not critical, and hence larger sugar spheres can be used in order to better control the dissolution rate.) that were sprayed with the melperone coating solution (15% solids) at 30–36
mL/min while maintaining the product temperature at 34
2°C and fluidization air volume at 100 CFM for a drug load of 20% or 25% by weight. A seal coat of Klucel®
LF dissolved in acetone/water was applied for a weight gain of 2%, and the resulting IR beads were dried to remove residual moisture and acetone.
Preparation of alkaline buffer coated melperone IR beads
Dibasic sodium phosphate anhydrous was dissolved in purified water and spray coated onto IR beads at a spray rate of 2
mL/min with a stepwise increase to 20
mL/min for a weight gain of 3.0% in a Glatt GPCG 3 equipped with a 6” bottom spray Wurster column, ‘C’ air distribution plate covered with a 200 mesh product retention screen, and 1.0
mm port size nozzle. Following completion of spraying and rinsing the spray system with acetone, a protective seal coat solution (Klucel LF dissolved in 85/15 acetone/water, 7.0% solids) was coated onto the disodium phosphate coated beads for a 2% coating weight gain at a product temperature of 33
2°C and a flow rate of 10
mL/min. The dried disodium phosphate coated IR beads were sieved to discard oversized beads and fines, if any.
Preparation of melperone SR beads
The alkaline buffer-coated IR beads were fluid-bed coated with an SR functional polymer coating formulation of ethylcellulose plasticized with dibutyl sebacate (DBS) at a ratio of 92.5/7.5 ethylcellulose/DBS dissolved in 85/15 acetone/water mixture (10% solids) at a product temperature of 33
1°C, atomization air pressure of 1.25 bar, inlet air volume of 15 CFM, and an initial flow rate of 8
mL/min with a stepwise increase to 20
mL/min for a SR coating level of 20%, 25%, or 30% by weight. Hydroxypropylcellulose (Klucel®
LF) dissolved in acetone/water was also coated onto the SR-coated beads to function as a compressible coating thereby minimizing the potential for fracture during compression of SR beads. The resulting SR beads were dried in the Glatt unit for five minutes to drive off residual solvents and sieved using 30 and 80 mesh sieves to discard oversized beads and fines (see for drug release profiles). Oversized beads are typically doubles, if at all formed, and may behave differently from normal coated beads in terms of lease profiles, especially upon compression, while fines are usually coating polymer fragments, if formed due to spray drying.
Melperone HCl release profiles from prototype SR bead formulations. Figure shows theoretical fast and slow release profiles and melperone release profiles from prototype SR beads coated at 15, 20, 25, and 30% by weight of the SR beads.
Preparation of melperone TPR beads
Melperone hydrochloride IR beads were coated with a TPR (timed, pulsatile release) coating composition comprising EC-10/HP-55/TEC (ethylcellulose 10 cps/hypromellose phthalate/triethyl citrate at a ratio of 70/20/10) dissolved in 90/10 acetone/water (10% solids) for a weight gain of 35% (relative to the weight of the coated bead) in a Glatt GPCG 3 equipped with a 7” bottom spray Wurster insert at an inlet temperature of 40–44°C and inlet air volume at 35 CFM. The TPR beads were further coated with the compressible coating of Klucel® LF at 2% by weight.
Preparation of rapidly dispersing microgranules
Rapidly dispersing microgranules were prepared following the procedure disclosed elsewhere13,14
. D-mannitol (152
kg) with an average particle size of approximately 20 µm or less (Pearlitol 25 from Roquette, France) was blended with cross-linked povidone (Crospovidone XL-10 from ISP) in a high shear granulator (GMX 600 from Vector), granulated with purified water (approximately 32
kg), wet-milled using a Comil from Quadro, and finally tray-dried to provide microgranules having an LOD (loss on drying) of about 0.8%. The dried granules were sieved, and oversize material was again milled to produce rapidly dispersing microgranules with an average particle size in the range of approximately 175–300 µm.
Preparation of melperone ODT-CR
Melperone hydrochloride SR beads (see for compositions of ODT-CR1 and ODT-CR2) were blended with rapidly dispersing microgranules, and other pre-blended pharmaceutically acceptable ingredients (i.e., peppermint or wintergreen flavor, sucralose, crospovidone, and microcrystalline cellulose) at a ratio of rapidly dispersing microgranules to melperone HCl SR beads of about 3:2 in a twin shell V-blender for a sufficient time to provide a homogeneously distributed blend for compression. The Hata tablet press was set up with appropriate punches and dies (15
mm flat face radius edge with no embossing) and the Matsui Ex-Lube system was set up to uniformly spray magnesium stearate onto the material contacting surfaces of the punches and dies at a desired spray rate. The hopper was filled with the compression mix. The compression parameters were adjusted to fill the dies with correct weights of the compression mix and compressed into tablets having a desired friability. After the main compression force equilibrated, 10 tablets were collected and tested for individual weights, thickness, hardness and friability. Once meeting the target weight (1
g), hardness (>30 N), and friability (≤0.6%), the press was operated in the ‘Auto’ mode to begin tableting. Tablets were periodically collected as a ‘composite’ and all compression attributes were recorded in the in-process compression data sheet of the batch record. Melperone HCl ODT-CR (50
mg) thus produced, rapidly disintegrated in the oral cavity creating a smooth, easy-to-swallow suspension comprising coated melperone HCl beads, and met the disintegration time specification of not more than 30
sec when tested by USP <701> method as well as provided a target in vitro
release profile suitable for a once-daily dosing regimen ().
Compositions and tableting properties of ODTs.
Melperone HCl release profiles from prototype ODT-CR formulations. Figure shows similar melperone release profiles from prototype ODT CR 161 and ODT CR 55 together with the corresponding SR beads.
Preparation of melperone CR capsules
Melperone hydrochloride IR beads were coated with a solution of EC-10 and PEG 400 at a ratio of 90/10 dissolved in 85/15 acetone/water (10% solids) for a weight gain of 20%, 25%, and 30% following the procedures as disclosed above, and dried in the Glatt GPCG 5 at approximately 33°C for 5 minutes to drive off residual moisture and acetone. Dried beads were sieved to discard oversize beads, if formed. An appropriate amount of the SR beads at a coating weight of 20% (247.5
mg), 25% (267.4
mg) and 30% (287.4
mg) were filled into hard gelatin capsules (approximately 6000 capsules of each formulation) using an MG-2 Futura 8400 equipped with a 4.8
mm dosing ring to produce 50
mg melperone hydrochloride CR capsules. demonstrates the in vitro drug release profiles from these capsules, matching the release profiles calculated from the two-compartment model as shown in .
Melperone HCl release profiles from prototype CR Capsule formulations. Figure shows varying release profiles from fast, medium, and slow release capsule formulations containing SR beads coated at different levels.
Analytical test methods
The analytical methods developed to test intermediate and finished products include the tests for identification, dissolution, assay/impurities, uniformity of dosage forms, moisture content, and residual acetone content. The SR beads, TPR beads, CR capsules and ODT-CR tablets were dissolution tested using USP Apparatus 2 (paddles@ 75 RPM) and a 2-stage dissolution media (testing at 37.0
0.5°C in 700
mL of 0.1N HCl for the first 2 hrs followed by testing for additional up to 22 hrs in 900
mL of pH 6.8 obtained by adding 200
mL of a pH modifier). Samples (1.5
mL) pulled at predetermined time points were tested for melperone by HPLC methodology (detector set at 248
nm) using Varian Pursuit XRs C18, 5 µm, 150
mm with guard column, 70:30 KH2
: acetonitrile (pH
0.05) mobile phase, 1.5
mL/min flowrate, and 10 µL injection volume. Beads, capsule contents, or ODT tablets were dissolved in acetonitrile, diluted with USP water, centrifuged and tested for melperone by HPLC. Individual unknown impurities were quantified by dividing the integrated areas of the individual unknown impurity peaks by the total area (i.e., melperone + sum of the individual impurities) while the individual specified identified impurities were quantified by dividing the individual area by the relative response factor of the corresponding impurity standard. The moisture content was determined by Karl Fischer titration method. Residual acetone contents were estimated by gas chromatograph equipped with a helium purged packed column and flame ionization detector. Disintegration times of ODT tablets were determined by current USP <701> without the use of disks and with USP water as the media.
Preparation of pilot CTM supplies
Melperone HCl ODT-CR tablets Test 1 (drug load: 20% w/w and SR coating: 30% w/w, see for composition) and Test 2 (drug load: 25% w/w and SR coating: 30% w/w, see for composition) comprising 50-mg melperone HCl as SR beads were manufactured under cGMP conditions by applying a drug layering, onto 45-60 sugar spheres, a protective seal coating, an alkaline buffer coating, and a protective seal coating (if present), and further applying an SR coating of ethylcellulose and dibutyl sebacate (92.5/7.5 Ethocel 10/DBS) for a weight gain of 25% w/w followed by a compressible coating of Klucel® LF at 2% by weight, blending with appropriate amounts of rapidly dispersing microgranules and other excipients (see for compositions), and compressing the blend as described previously.
Melperone HCl CR Capsules (Test 3) containing 50-mg melperone HCl as SR beads were manufactured under cGMP conditions by coating IR beads at a drug load of 25% by weight using 25-30 mesh sugar spheres for drug layering/protective seal coat of Klucel LF at 2% by weight, with ethylcellulose and polyethylene glycol 400 (92.5/7.5 Ethocel 10/PEG 400) for a weight gain of 25% w/w and filling appropriate amount of SR beads into size # 1 hard gelatin capsules, as described previously (see for the release profiles).
In vitro drug release profiles of pilot CTM supplies – ODT-CR (Test 1 (fast release) & Test 2 (medium release) contain an alkaline buffer layer and smaller inert cores) and CR Capsule (Test 3 contain larger inert cores without an alkaline (more ...)
Pilot PK studies
A single-dose, randomized, crossover study was conducted using healthy adult subjects under fasting conditions to assess the pharmacokinetics of four treatments: 25 and 50-mg syrup, 50-mg Test 1 (ODT-CR 1 [fast]), 50
mg Test 2 (ODT-CR 2 [medium]), and 50-mg Test 3 (CR capsule). The melperone plasma concentration vs. time profiles are illustrated in . Dose normalized least square mean PK parameters and 90% confidence intervals for reference (melperone syrup), and Test 1, test 2, and Test 3 are presented in and .
Plasma concentration-time profiles of pilot CTM supplies – Syrup 25-mg, ODT-CR (Test 1 (fast release) & Test 2 (medium release)), and CR Capsule (Test 3).
PK parameters for melperone treatments A (25-mg Syrup; 50-mg Syrup), B (50-mg ODT-CR 1), C (50-mg ODT-CR 2), and D (50-mg CR Capsule).
Melperone plasma PK data - least-squares means and 90% CIs.
Pilot CTM supplies including melperone HCl CR capsules, ODT-CR 1 (fast) and ODT-CR 2 (medium) packaged in 60 cc (capsules) or 75 cc (ODTs) induction-sealed, HDPE bottles (30 counts) were subjected to stability evaluation per International Committee on Harmonization guidance for 6 months. The stability data are presented in .
Stability data for Melperone CR Capsules and ODT-CR 2.
Manufacture of melperone SR beads at one-tenth commercial scale
Melperone hydrochloride (15.0
kg) was dissolved in 50/50 mixture of acetone and water (50
kg each), with constant stirring. A Glatt GPCG 120 equipped with an 18” bottom spray Wurster 23.75” column; outer “G” and inner “C” bottom air distribution plate covered with a 100 mesh product retention screen, partition height: 50
mm; nozzle port size: 3.0
mm with HS Collar; was charged with 43.8
kg of 45–60 mesh sugar spheres. The above melperone solution was sprayed onto the sugar spheres at an initial rate of 100
g/min with ramp up (range: 75–700
g/min); inlet air volume: 450 CFM (range: 500–900 CFM); set process air temperature: 45°C (range: 39–65°C); atomization air pressure: 2 bar; target product temperature: 32°C (range: 29–36°C). Following rinsing of the spray system with 50/50 acetone/water, a sealant solution (Klucel LF dissolved in 85/15 acetone/water, 7.5% solids) was sprayed onto the melperone-coated beads at an initial rate of 200
g/min and a stepwise increase to 300
g/min, and process air temperature of 45°C (range: 35–50°C). The resulting sealant-coated beads (Klucel®
LF coating at 2% w/w) were then dried in the Glatt unit for 5
min. to drive off residual solvents. The resulting IR beads were sieved to discard oversized (>500 µm or 35 mesh) beads and fines (<80 mesh).
Dibasic sodium phosphate anhydrous (DPA; 6.2
kg) was dissolved in 124
kg of purified water while stirring. Melperone hydrochloride IR beads (52.6
kg) were coated with the aqueous alkaline buffer solution at a fluidization air volume of 650 CFM (range: 400–800 CFM); atomization air pressure: 2.5 bar, target product temperature: 53°C (range: 49–60°C); spray rate: 100
g/min with ramp up to 400
g/min (range: 75–700
g/min). Following the buffer layering, a protective seal coat with an Opadry Clear aqueous solution (6% solids) was applied to the DPA coated beads for a weight gain of about 2% (relative to the weight of the seal-coated beads) at a product temperature of 50°C and a flow rate of 200
g/min (range: 100–350
g/min). The seal-coated beads were then dried in the Glatt unit for not more than 5
min. to drive off residual solvents.
Ethylcellulose, EC-10 (13.9
kg) was slowly added to 85/15 acetone/water mixture (214.2
kg), with stirring, until dissolved. Dibutyl sebacate (1.1
kg) was then slowly added to the polymer solution and stirred for 30
min. The buffer-coated melperone IR beads (34.0
kg) were charged into a Glatt GPCG 120 equipped with an 18” bottom spray Wurster 18” column, 3.0
mm nozzle port with HS Collar and bottom inner “G” and outer “C” distribution plate, and coated with the above SR coating solution (7% solids) at an initial rate of 100
g/min with ramp up to 500
g/min (range: 75–700
g/min); inlet air volume: 500 CFM (range: 400–900 CFM); process air temperature: 64°C (range: 40–70°C); atomization air pressure: 2.5 bar; target product temperature: 33°C (range: 29–40°C). Following rinsing with acetone, the SR-coated beads were sprayed with a compressible coating solution (Klucel® LF dissolved in 85/15 acetone/water, 7.5% solids) at an initial rate of 200
g/min (range: 100–350
g/min); process air temperature: 45°C (range: 35–50°C); product temperature: 32°C (range: 28–40°C), and then dried in the Glatt unit for 5
min. to drive off residual solvents (including moisture).
Pharmaceutically acceptable ingredients (i.e., peppermint flavor, sucralose, crospovidone, and microcrystalline cellulose; see ) were first blended in a V blender to achieve a homogeneously blended pre-mix. Rapidly dispersing microgranules were blended with the melperone HCl SR beads and the pre-mix in a twin shell V-blender for sufficient time to obtain a homogeneously blended compression mix, which was compressed into ODT tablets using the production scale Hata tablet press equipped with an external lubrication system (Matsui ExLub System) and round, flat faced, radius edge tooling, under tableting conditions fine-tuned for optimal performance. Two ODT batches were produced as described above, having different tablet weights and relative amounts of melperone SR beads and rapidly dispersing granules, and these tablets exhibited the tableting properties shown in and .
Compositions and tableting properties of ODTs.
Figure10. Drug release profiles of ODT formulations and corresponding SR beads manufactured at one-tenth commercial scale. Figure shows minimum membrane fracture when compressible coated SR beads tableted with rapidly dispersing microgranules at different ratios (more ...)