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									 ChE 702-002: Modules in Nanopharmaceuticals, Spring 2007




    Generation of Phenytoin particles and
      drug-polymer solid dispersions by
    means of compressed gas precipitation




Micaela Caramellino                          mc246@njit.edu


                                                              1
                            Papers


1   Dense Gas Antisolvent Precipitation: a comparative
      investigation of the GAS and PCA techniques
    F. Fusaro, M. Hanchen, M. Mazzotti, G. Muhrer, B. Subramaniam
                     Ind. Eng. Chem. Res., 2005


2   Use of compressed gas precipitation to enhance the
    dissolution behavior of a poorly water-soluble drug:
    Generation of drug microparticles and drug-polymer
                     solid dispersions

       G. Muhrer, U. Meier, F. Fusaro, S. Albano, M. Mazzotti
                Int. Journal of Pharmaceutics, 2006
                                                                    2
                              Outline


Goal: elucidating the potential of gas antisolvent and precipitation
with compressed antisolvent processes to enhance the dissolution
behavior of poorly water-soluble drugs by investigating the
micronization of neat drug substance and the generation of drug-
polymer co-formulations.


              Outline:
              • Description of the processes involved
              • GAS experiments
              • PCA experiments
              • Co-precipitation experiments


                                                                       3
                         Processes

Gas Antisolvent (GAS) precipitation


       Technique for precipitating or crystallizating
       solutes dissolved in a liquid solvent system by
       addition of a supercritical antisolvent



Rapid Expansion of Supercritical solutions (RESS)

       Technique for precipitating solutes dissolved in
       a supercritical solution by means of a sudden
       pressure change



                                                          4
       Processes


             GAS




RESS

                   5
               Processes

PCA - Precipitation with compressed antisolvent




                                                  6
 Precipitation of Phenytoin – GAS experiments




          Initial phenytoin conc.


M0 = amount of starting solution    Operating conditions:
                                    V = 400ml
MA = rate of antisolvent addition
                                    T = 30°C
QA = MA/M0
                                    n = 400rpm
                                                            7
     Precipitation of Phenytoin – GAS experiments
- Effect of the specific antisolvent addition rate (QA)

               QA = 0.07                                           QA = 0.1



      S0 (initial
   saturation ratio)
  was kept constant


   Higher value of
   nucleation rate



               QA = 0.2                                            QA = 0.5

   The average crystal size and volume decreases when QA is increased 8
  Precipitation of Phenytoin – GAS experiments

- Effect of the solvent


                                  Acetone – G3


   Operating conditions:
   V = 400 ml                     75 % vol. ethanol
   T = 25°C                       25% vol. acetone
   n = 400 rpm                    G11
   QA=0.2 min-1
   M0=50 g

                                  Ethanol – G8


                                                      9
Precipitation of Phenytoin – PCA experiments




                                           10
    Precipitation of Phenytoin – PCA experiments
- Effect of temperature and pressure



                                        P=150 bar (P5)




                                        P=120 bar (P4)

         CO2-acetone system


                                        P=95 bar (P3)
        The experimental point
        approaches the mixture
             critical point
                                                 11
    Precipitation of Phenytoin – PCA experiments

- Effect of temperature and pressure

  Lengsfeld et al., 2000
     In the supercritical mixture region, due to the vanishing of the
     interfacial tension and the fact that solvent and antisolvent become
     fully miscible, fluid mixing rather than jet break-up into droplets
     becomes the controlling mechanism for particle formation.

  For drug particles
     The distance from the critical region affects the shape of the final
     particle – different fluid flows regimes appear:
     -Droplet formation in the sub or near-critical region two phase
     region
     -Gas-like jet in the supercritical region


                                                                            12
    Precipitation of Phenytoin – PCA experiments
- Effect of the flow rate ratio
                                               MA to MSOL ratio of 60 (P6)

 The ratio between the solution flow rate
 and the CO2 flow rate controls the
 supersaturation level that can be reached
 in the injection device
  For the experimental conditions of the
 runs considered, it is expected particle
 formation to be controlled by mixing rater
 than by jet break-up into droplets



  Increasing MA relative to MSOL yields to
  a product containing both needles and
  crystals
                                              MA to MSOL ratio of 160 13
                                                      (P7)
   Precipitation of Phenytoin – PCA experiments

- Effect of the initial concentration




                                              14
     Precipitation of Phenytoin – PCA experiments

  - Effect of the initial concentration



     P9 – 2%                              P8 -3%

Needles up to
200 mm                                     Needles




Decrease in the                           Particles
needles length                            highly
                                          agglomerated

    P10 – 3%                              P1 - 4%


                                                     15
Precipitation of Phenytoin – PCA experiments




Particles size
 for different
     runs




                                           16
Drug-polymer coformulations of phenytoin and PVP



      PCA and GAS used for generating solid dispersions of
        poorly water-soluble compounds in water-soluble
                        polymeric carrier




          Compare the in vitro dissolution behavior with
          particles obtained with spray-dried technique




                                                             17
Drug-polymer coformulations of phenytoin and PVP
First experiment:
         GAS recrystallization of PVP-K30 from ethanol/acetone mixtures
                                         Liquid-liquid phase separation
   Initial concentration: 0.5 – 8% wt.
                                         yielding large porous,
   Operating temperature: 5 - 30°C       interconnected polymer
   CO2 addition rate: 0.5-2 min-1        structures rather than discrete
                                         particles.

Second experiment:
       PCA precipitation of pure PVP-K30 microparticles
     Ethanol/acetone mixture
     (24% wt. ethanol) as organic
     solvent phase
                                             Better results
     Operating pressure below the
     critical pressure of the binary
     system (80 bar)
     Operating temperature: 25°C                                      18
         PCA co-precipitation experiments

Possibility of molecularly dispersing phenytoin in a continuous matrix
           of polyvinyl-pyrrolidone to form a solid dispersion




            Ethanol/Acetone mixture (24% wt. ethanol)
            Pressure = 80 bar
            Temperature = 25°C                                       19
          PCA co-precipitation experiments

Taki et al. (2001)
   The relative concentration of active agent and polymer was
   reported to have a decisive influence on the encapsulation
   efficiency


Effect of the relative amount of
phenytoin and PVP-K30


 Ratios between 1:4 and 1:2 :
 The co-precipitate appears as
 agglomerates of spherical
 primary particles – below 500
 nm in size – no needle like
 crystals                                  1:4 ratio drug to polymer
                                                                   20
            PCA co-precipitation experiments

Effect of the relative amount of
phenytoin and PVP-K30


      When the concentration of phenytoin in the
      initial solution is small compared to the
      concentration of PVP-K30 (ratios of less than
      1:2), the product appears as micron size
      agglomerates of spherical nanoparticles that
      were completely amorphous and showed no
      recrystallization tendency after several weeks
      of storage.


                        At higher drug concentrations no true solid
                        solutions were formed anymore

                                                                      21
          PCA co-precipitation experiments

                           PCA co-precipitation
Dissolution performances
                           Spray drying

                                          -The drug if first
                                          tabletted (know
                                          and constant area)
                                          - then it is
                                          contacted with the
                                          dissolution medium


                                          The dissolution rate
                                          is proportional to
                                          the particle size
                                          and PSD              22
             PCA co-precipitation experiments
Dissolution performances


PCA run P3
                      Spray drying        PCA run C1        PCA




High pressure hom.               Physical mixture      Spray drying

               Dissolution rate = slope of the curve
                                                             23
          PCA co-precipitation experiments


Dissolution performances


      The increase in the dissolution rate is
      - up to eight-fold when compared to pure drug
      particles
      - 25% when compared to spray-dried solid
      dispersions


                     The increase is more evident with increasing
                     the polymer content


                                                                    24
                 Conclusions



 Compressed fluid antisolvent precipitation is
an efficient method for oral bioavailability
enhancement of poorly water-soluble
compounds
 A parametric analysis has been successfully
conducted
 The study needs to be extended to higher
polymer contents to optimize the dissolution
performance


                                                  25

								
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