Solkane® 227 pharma and 134a pharma (NEW) - Properties

Solubility Parameters/Characteristics Solubility Values Solubility in  Solkane® 227 pharma Solkane® 134a pharma  Water[18] at 20°C, 68°F ppm  58 193 Octanol[18] at 20°C, 68°F ppm  5.070  2.140   Solubility in HFA 227 and HFA 134a of    Oxygen[19] at atmospheric conditions: at 25°C (77° F), in liquid phase g/kg     approx. 0.08   approx. 0.10 Nitrogen[16] at atmospheric conditions: at 25°C (77° F), in liquid phase g/kg     0.55   0.15 Water[18] Measured values at 25°C in liquid phase[18]     g/kg     0.61   2.20 Experimental results inliquid phase at 25°C [26] g/kg     n.d. 1.21 Ethanol[18]   Miscible   Miscible Silicone Oil[19] high viscosity oil (V1000) ppm(wt.) 149    317  Silicone Oil[19] low viscosity oil (V300) ppm(wt.) 585    505    Solubility Characteristics Dipole Moment measured value liquid phase debye  0.93 [14]    2.058 [15] Dipole Moment calculated value gas phase [14] debye  1.46    n.d. Octanol-Water-Coefficient [16] log Pow  2.05    1.06 Kauri-Butanol-Index    13[18]    9.2[17] Solubility Parameter calculated value [18]    5.4   6.8   Solubility of Water There is a notable difference in water solubility between HFA 227 and HFA 134a. As shown in Fig. 21, the moisture uptake of HFA 134a is six times higher compared to HFA 227 (measured values) due to its higher polarity. Therefore HFA 227 is preferred for formulations which might change due to water uptake during the MDI shelf life, e.g. for drugs such as sodium cromoglycate, cromoglycic acid, nedocromil sodium, nedocromil, ipratropium bromide, salbutamol sulfate, terbutaline hemisulfate or formoterol. In general, the HFAs are more polar than CFCs and thus more hygroscopic. Dipole Moments[16] HFA 134a   2.06 H2O   1.85 Ethanol   1.68 HFA 227   1.46; (0,93) [14] CFC 114   0.66 CFC 12   0.51 CFC 11   0.45   Water Solubility in HFA 134a Fig. 20: Illustration of the experimental results for water solubility in HFA 134a in liquid phase [20, 21]   Moisture Uptake Sources of Moisture Uptake in MDIs: Due to partial pressure differences inside and outside of the MDI, moisture uptake takes place by diffusion. Possible Effects of Moisture Uptake: Improves solubility of polar substances in the propellants Reduces the solubility of lipophile, hydrophobic substances Increases probability that sensitive substances become oxidised during shelf live Increases the corrosion risk of aluminium cans over the shelf life Agglomeration of suspended drug substances Influences the discharge behaviour of the active substances Solubility of Oxygen and Nitrogen Solubility of Nitrogen in HFA 134a Solubility of Oxygen During the manufacture of MDIs (metered dose inhalers), organic molecules (for example active substances e.g. sodium cromoglycate), tensides (e.g. oleic acid) and solubilisers e.g. ethanol) are suspended or solubilised in HFA 227 and/or HFA 134a. Because organic molecules can be oxidised by oxygen, it is important for the manufacture of MDIs to know the solubility of oxygen in the propellant being used (such as Solkane® 227 pharma and Solkane® 134a pharma).   Gases like oxygen and nitrogen always form equilibria with pressurised liquefied gases in the gas phase and the liquid phase. These equilibria depend on temperature, filling factor and total pressure. Therefore, the figures show precisely determined values but only for one temperature, one filling factor and a specific amount of gas. The most important result is that there is a big difference between the oxygen and nitrogen content in the gas phase compared to the liquid phase.      Fig. 23/24: Typical content of oxygen and nitrogen in Solkane® 227 pharma and Solkane® 134a pharma   Influence of Ethanol on HFA227 and HFA 134a Ethanol is widely used as an exipient in pharmaceutical formulations for MDIs because of its miscibility with the HFA propellant and the positive influence on the solubility of organic molecules due to the higher polarity. The addition of ethanol increases the polar/hydrophobic characteristics of a formulation. The addition of ethanol also increases the moisture uptake capacity of the MDI formulation. Furthermore, in the case of HFA 134a the addition of ethanol slightly reduces the pressure of the propellant. Adding ethanol to a formulation also reduces the density of the mixture. The pressure versus mixture curves (Fig. 25) were derived from measured data (Hoechst 90/91).     Chemical Behaviour Material Compatibility The material compatibility is tested to determine the specifications for materials suitable for the manufacture of pharmaceutical aerosols (e.g. composition of seals, metering chambers, gaskets, seats or stems). Aspects analysed include changes in weight, volume, length, width, shore hardness, appearance (e.g. bubble formation), permeability of water and amount of extractables.   Classification of Materials for Use in MDIs   HFA 227 HFA 227 and HFA 134a HFA 134a Sealing Material CR, NBR, NR, EPDM(5), PVC(6), PCTFE(6), PA(6), PBT(6), PP(6)  PTFE(6), IRR  HNBR, POM, PET General Use NBR, IRR, POM PTFE, PCTFE, PBT, PA, CR, NR  HNBR Not Recommended HNBR(4) FPM(1), PE(3)  NBR(2), EPDM(2) (1) Strong swelling behaviour and presence of bubbles (2) Permeability of water (3) Bubble formation on material surface (4) Strong swelling (5) Recommended in the absence of mineral oil or alkyl benzene (6) If technical specification designs allow, e.g. PTFE used in connection with metal joints   Fig. 27: Extractables from plastics: 1.) Polyethylene (PE), 2.) Polyamide 6.6 (PA), 3.) Polyacetal (POM), 4.) Poly(butylene terephthalate) (PBT), and 5.) Polypropylene (PP) after immersion in HFA 227/5 wt % EtOH and HFA 134a/5 wt % EtOH for 500 h at 80°C; Polytetrafluoroethylene (PTFE) produced zero extractables   Fig. 28: Extractables from elastomers 7.) Acrylonitrile-butadiene rubber (NBR), 8.) Ethylene-propylene-diene rubber (EPDM) and 9.) Chloroprene rubber (CR) after immersion in HFA 227/5 wt% EtOH and HFA 134a/5 wt % EtOH for 500 h at 80°C     Evaluation Criteria for Material Compatibility There is a large range of elastomers and plastics on the market with different trade names which are made of similar raw materials and which are only distinguished by certain additives. These additives may affect the thermal and mechanical stability, the swelling properties, as well as the resistance to aging of elastomers and plastics. When assessing complete systems, it is necessary to include the compability characteristics of the drug formulation.     Solkane® 227 pharma  Solkane® 134a pharma 1. Metals/Valves/Fittings/ Vessels/Cans HFA227 and HFA 134aare compatible with mild steel, stainless steel, CuBe2 membranes, brass and aluminium, black sheet iron, copper and galvanised sheet metal when the presence of water can be excluded. Water content might lead to an increase in corrosion, with the exception of 1.4551 V2A–steel. Material ISO 1629 Chemical Abbr. Trade name Compability   Compability  2. Elastomers1 Chlorobutadiene rubber CR Neoprene® + + Hydrated acrylonitrilene- butadiene rubber HNBR Perbunan® Bayprene® Tomac® o + Natural rubber NR Dynaprene® + + Butyl rubber IRR Europrene® + + Fluorinated rubber FPM Viton®, Fluorel®, Tecnoflon® –   –  Acrylonitrile- butadiene rubber NBR Perbunan®N Krynal®, Hycar®, Chemigum® + o Ethylene- propylenediene rubber EPDM Nordel® + o 3. Plastics Polytetrafluoroethylene PTFE Hostaflon® TFM, Algoflon® + + High density polyethylene HDPE Alathon®, Eltex® o o Polyacetal POM Hostaform® C9021 + + Polyphenylene sulfide PPS Fortron®, Rylon® * + Liquid crystal polymers LCP Vectra® * + Polyester fibre PET Trevira®, Hostaplast®, Hostaphan® * + Polyvinylchloride PVC Hostalit®, Solvin® + + Polychlorotrifluoro ethylene PCTFE + + Polyamide PA Isonamid® + + Polybutylene- terephtalate PBT Celanex® X 5002, Valox®, Arnite® + + Polypropylene PP Adell®, A-Fax®, Eltex P® + + Polystyrene PS Styron®  *  o 1According to ASTM D 1418-01  + compatible / o borderline / – incompatible / *no information, tests required     Back