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CPM : HPC-SSL HMM

Dissolution Enhancement and Controlled Release

Processing techniques for low viscosity hydroxypropylcellulose polymers

CPM : HPC-SSL HMM CPM : HPC-SSL PM

Heat Flow (W/g)

CPM : HPC-SL PM CPM

L
80 100 Temperature (C) 120 140
Universal V4.5A TA Instruments

ow viscosity HPC-SL and SSL can be employed to produce chemically stable SDs of poorly- as well as highly water-soluble drugs using various pharmaceutical processes in order to control API dissolution.

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Materials and Methods

Preparation of Physical Mixtures (PMs). Carbamazepine (CBZ), phenytoin (PHT), and chlorpheniramine maleate (CPM) were mixed with the polymers at 25:75 drug-polymer ratio using mortar and pestle followed by turbula mixing to prepare PMs. The PMs were then compacted, milled and the sieved fractions between 250-420 m were used. Preparation of Physical Mixtures (PMs). The drugs were mixed with the polymers at 25:75 drug-polymer ratio using mortar and pestle followed by turbula mixing to prepare PMs. The PMs were then compacted, milled and the sieved fractions between 250-420 m were used. Hot Melt Mixing (HMM). The PMs were mixed at 150 rpm for 5 minutes in Brabender hot melt mixer at 150, 180, 180, and 130C for CBZ, HCTZ, PHT, and CPM, respectively to manufacture HMM formulations (HMMs). The HMMs were milled and the sieved fractions between 250-420 m were used. Ball Milling (BM). The PM of PHT : HPC-SSL was ball milled at 400 rpm for 30 minutes using 50 pieces of 10 mm balls. The BM was then compacted, milled and the sieved fractions between 250-420 m were used. Solvent Evaporation (SE). SE of PHT : HPC-SSL PM was performed using Rotavap at 40-50C and 150-200 rpm for 30 minutes. Drying was carried out in vacuum oven at 40C for 12 hours. The milled SE was sieved and fractions between 250-420 m were used. Differential Scanning Calorimetry (DSC). Approximately 5 to 7 mg of the samples were subjected to heat cool heat cycle with heating rate of 10C/min and the cooling rate of 50C/ min. Polarized Light Microscopy (PLM). The samples were smeared using mineral oil and observed with 10x magnification using polarized light microscope. HPLC Analysis. HPLC analysis of the HMMs was performed using Agilent Zorbax Eclipse XDB-C18 (4.6 x 250 mm) column. Acetonitrile and water in the ratio of 30:70 v/v was used as the mobile phase for CBZ, PHT, and HCTZ. The mobile phase of pH 3.9 adjusted using concentrated HCl containing water, acetonitrile, and triethyl amine in the ratio of 64.9:32.7:2.4 v/v was used for CPM. Dissolution Study. The dissolution experiments were performed at 37 0.5C and 50 rpm in 900 ml 50 mM phosphate buffer of pH 6.8 or 0.1N HCl using dissolution apparatus II. The milled formulations of CBZ, PHT, and HCTZ were filled in size zero capsules with sinkers, whereas CPM formulations were compressed into tablets. The dissolution samples were analyzed using UV detector in 96 well costar clear plates at 285, 250, 271, and 265 nm for CBZ, PHT, HCTZ, and CPM, respectively.

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Figure 1: First heating cycle DSC plots of CPM, its PMs, and HMMs formulated with HPC-SL and HPC-SSL.

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Nisso America/University of Rhode Island Poster

Results and Discussion

Differential Scanning Calorimetry (DSC). Amorphous conversion of CPM and CBZ occurred during HMM process could be detected by observing disappearance of melting endotherm, but that of HCTZ and PHT could not be identified near their very high melting temperatures due to probable degradation of the polymers. HPC polymers significantly depressed the melting points of CPM and HCTZ. Polarized Light Microscopy (PLM). The birefringence of crystalline drug observed in the PLM images of PMs was significantly reduced in the HMMs for CPM and CBZ with HPC polymers. However, significant birefringence was observed in the PLM images of HMMs of PHT and HCTZ compared to their PMs using all the polymers. Further, amorphous conversion of PHT with HPC- SSL could not be achieved using other processes such as BM and SE, and significant birefringence was detected in their PLM images. HPLC Analysis. Chemical stability of all the drugs was better maintained by HPC and PVP-VA during HMM process compared to other polymers. On the other hand, significant acid catalyzed degradation of CBZ with anionic polymers and HCTZ with cationic polymer was detected in their HMMs. Dissolution Study. The dissolution rate and extent of neutral drug CBZ was significantly improved over 5 hours using the polymers due to amorphous transformation. The highest dissolution rate of CBZ : Eudragit EPO system could be due to very high solubility and dissolution rate of the polymer in 0.1N HCl. Although the dissolution rate of CBZ : PVP-VA HMMs was highest amongst the nonionic polymers, HPC polymers also exhibited significant improvement in dissolution rate and extent compared to the pure drug. Unlike CBZ, the dissolution rate and extent of weakly basic drug - HCTZ itself was relatively high. The crystalline solid dispersions of HCTZ that could

Table I: Percent of theoretical drug remaining in each formulation after HMM processing, as determined by HPLC (data represent the average of two independent assayed samples).
Polymer Percentage of API Remaining CBZ HCTZ PHT CPM

HPC-SL HPC-SSL HPMCAS-LF PVP-VA

97.07 98.77 78.66 104.95

95.36 95.34 102.44 95.80 94.02 54.63

99.42 100.07 96.57 100.19 104.00 97.03

100.50 100.14 N/A N/A N/A N/A

Eudragit L-10035.18 55 Eudragit EPO 101.33

Figure 2: First heating cycle DSC plots of PMs of (a) CBZ, (b) PHT, and (c) HCTZ; and HMMs of (d) CBZ, (e) PHT and (f) HCTZ formulated with various polymers.

(a)
8
CBZ : PVP-VA

(d)
8
CBZ : PVP-VA

6 4 Heat Flow (W/g) 2

CBZ : Eudragit EPO CBZ : Eudragit L-100-55

6 4 Heat Flow (W/g) 2

CBZ : Eudragit EPO CBZ : Eudragit L-100-55 CBZ : HPMCAS-LF

CBZ : HPMCAS-LF CBZ : HPC-SSL

CBZ : HPC-SSL

0 -2 -4 -6

CBZ : HPC-SL CBZ

0 -2 -4 -6

CBZ : HPC-SL CBZ

50

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100 150 Temperature (C)

200

250
Universal V4.5A TA Instruments

50

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100 150 Temperature (C)

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250
Universal V4.5A TA Instruments

(b)
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PHT : PVP-VA

(e)
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PHT : PVP-VA

2 0 Heat Flow (W/g) -2 -4 -6 -8 -10 -12

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PHT : Eudragit L-100-55 PHT : HPMCAS-LF

2 0 Heat Flow (W/g) -2 -4 -6 -8 -10 -12

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PHT : Eudragit L-100-55 PHT : HPMCAS-LF PHT : HPC-SSL PHT : HPC-SL PHT

PHT : HPC-SSL PHT : HPC-SL PHT

50

100

150 200 Temperature (C)

250

300

Universal V4.5A TA Instruments

350

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150 200 Temperature (C)

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350

(c)
HCTZ : PVP-VA

(f)
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HCTZ : PVP-VA HCTZ : Eudragit EPO HCTZ : Eudragit L-100-55

HCTZ : Eudragit EPO HCTZ : Eudragit L-100-55

Heat Flow (W/g)

Heat Flow (W/g)

HCTZ : HPMCAS-LF

1
HCTZ : HPMCAS-LF HCTZ : HPC-SSL

HCTZ : HPC-SSL

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HCTZ : HPC-SL HCTZ

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HCTZ : HPC-SL HCTZ

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300

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Nisso America/University of Rhode Island Poster

Figure 3: PLM images of (a) CPM : HPC-SL PM, (b) CPM : HPC-SL HMM, (c) CBZ : HPC-SSL PM, and (d) CBZ : HPC-SSL HMM.

Figure 6: Dissolution profiles of milled HMMs of CBZ using various polymers (as shown in Table I, degradation of CBZ was detected in HMMs with the anionic polymers HPMCAS-LF and Eudragit L-10055. Their dissolution profiles are not included).
Percent Drug Dissolved 100 80 60 40 20 0 0 60 120 180 Time (min) PVPVA Pure Drug 240 300 HPC-SL

Eudragit EPO HPC-SSL

Figure 4: PLM images of (a) PHT : Eudragit EPO PM and (b) PHT : Eudragit EPO HMM; (c) PHT : HPMCAS-LF PM and (d) PHT : HPMCAS-LF HMM; (e) HCTZ : Eudragit L-100-55 PM and (f) HCTZ : Eudragit L-100-55 HMM; (g) HCTZ : PVP-VA PM and (h) HCTZ : PVP-VA HMM.

Figure 7: Dissolution profiles of milled HMMs of HCTZ using various polymers (As shown in Table I, degradation of HCTZ was detected in HMMs containing the basic polymer Eudragit EPO. Its dissolution profile is not included).

Percent Drug Dissolved

Figure 5: PLM images of PHT : HPC-SSL (a) PM, (b) BM, and (c) SE formulations.

100 80 60 40 20 0 0 60 120 180 240 Time (min) 300

Eudragit L-100-55 PVPVA HPC-SSL

be manufactured by HMM using non-ionic polymers PVP-VA and HPC depicted dissolution profiles similar to the pure drug. On the other hand, HMMs of HPMCAS-LF and Eudragit L-10055 showed slight improvement in the dissolution rate compared to the pure drug, which could be due to counter ionic interactions between weakly basic HCTZ and these anionic polymers. The dissolution rate and extent of PHT was slightly enhanced by both non-ionic (HPC) and anionic (HPMCAS-LF and Eudragit L-100-55) polymers due to formation of crystal-

HPMCAS-LF HPC-SL

Pure Drug

line solid dispersions of the drug in these hydrophilic polymers during HMM process. However, dissolution of PHT was significantly reduced for PHT : PVP-VA HMMs, probably due to formation of hydrophobic lumps during dissolution that didnt disperse and/or erode rapidly. The significant enhancement in dissolution of weakly acidic PHT using cationic Eudragit EPO could be attributed to counter-ionic drug-polymer interactions as well as very high solubility and dissolution rate of the polymer in 0.1N HCl.

Nisso America/University of Rhode Island Poster

Figure 8: Dissolution profiles of milled HMMs of PHT using various polymers.

Percent Drug Dissolved

Figure 9: Dissolution profiles of PHT formulated with HPC-SSL using various processing techniques.

100 80 60 40 20 0 0 60 120 180 240 Time (min) HPC-SL PVPVA 300 HPC-SSL

Percent Drug Dissolved

100 80 60 40 20 0 0 60 120 180 Time (min) PM 240 300

Eudragit EPO Eudragit L-100-55 Pure Drug

HPMCAS-LF

Solvent Evaporation HMM

Ball Mill Pure Drug

Figure 10: Dissolution profiles of CPM tablets containing HMMs and PMs formulated with HPC-SL and HPC-SSL in (a) 0.1N HCl and (b) phosphate buffer pH 6.8.

(a) Percent Drug Dissolved

100 80 60 40 20 0 0 60 120 180 240 300

(b) Percent Drug Dissolved

100 80 60 40 20 0 0 60 120 180 240 300

Time (min) HPC-SSL-HMM HPC-SL-PM

Time (min) HPC-SSL-HMM HPC-SL-PM

Although the drug could not be converted into its amorphous form using any of the processes, the enhancement in dissolution of PHT was in the order of SE, BM, HMM, and then PM compared to the pure drug, probably due to more intimate mixing and that could have occurred during SE and BM compared to HMM. Controlled release of BCS class I drug CPM could be achieved at both gastric and intestinal pH using HPC polymers. Better controlled release of PMs over HMMs could

be attributed to amorphous conversion, whereas that of SL grade over SSL grade could be due to higher viscosity of the SL grade.

This poster was produced through the joint cooperation of Nisso America and the University of Rhode Island Colleges of Pharmacy and Engineering and was originally presented at the 2012 AAPS Annual Meeting in Chicago. For additional information visit NissoExcipients.com.