Bauer· Lehmann· Osterwald · Rothgang
`
`0
`Pharmaceutical
`Forms
`
`KASHIV1052
`IPR of Patent No. 9,492,392
`
`

`

`KASHIV1052
`IPR of Patent No. 9,492,392
`
`

`

`86
`
`Film Coatings
`----~----------------------------------------------------
`
`thereby providing stable latex-like systems
`[81]. For this purpose, 350 ml of demineral-
`ized water are given into a one-liter three-
`necked glass tlask, equipped with reflux con-
`denser, high-speed stirrer and contact ther-
`mometer, whereupon 150 g of ground poly-
`mer are suspended in this water. Stirring is
`performed al 400 to 1200 rpm, with simul-
`taneous heating to 80 oc. This temperature is
`maintained for 2 hours and stirring then con-
`tinued without heating. At the end of the
`process, milky-viscous, stable dispersions
`with particle sizes between15 and 150 nm are
`obtained [141].
`
`Dispersion of Polymer Salts
`Salt-forming functional groups in polymers
`show shifting pK values, rSince each ionic
`group formed influences the protonation or
`deprotonation of the neighboring groups,
`causing the addity or basicity of the remain-
`ing groups to decrease continuously. Salt for-
`mation thus extends over a wide pH range.
`The hydrophilicity increases with the degree
`of neutralization, and the ionic groups of like
`charge help to stretch and uncoil the polymer
`molecules until the polymeric salt dissolves at
`a particular degree of neutralization. This de-
`pends on the content in salt-forming groups
`and hydrophobic regions, but often occurs at
`20 to 60% neutralization. In the transition
`range, where salt formation has already
`caused noticeable hydrophilicity in several
`regions of the polymer molecule without dis-
`solution taking place, dispersion of the poly-
`mers may be facilitated and latex-like disper-
`sions be formed which are stabilized by the
`charges of the ionized groups. This effect of
`partial neutralization is utilized for redispers-
`ing polymer powders [80].
`
`Redispersion of Dried Latexes
`Suitable drying conditions for latexes can be
`selected to prevent film formation occurring
`and to obtain isolated latex particles in the
`
`dry powder [48]. Spray drying can even be
`performed above the minimum film-forming
`temperature, since the evaporating water
`strongly cools the spray droplets and the
`capillary forces responsible for film forma-
`tion are virtually ineffective. Freeze drying
`can be used for dispersions from soft poly-
`mers ·with low film-forming temperatures.
`Under certain conditions, latexes can he re-
`constituted from dry powders consisting of
`loose agglomerates of unfilmed, isolated
`latex particles. This process is aided by emul-
`sifiers and plasticizers, salt formation at the
`polymer molecule, and use of stirring equip-
`ment with controlled shear forces [141].
`
`4.2.4.3.3 Mechanism of Film
`Formation
`Polymer dispersions show a special film-
`forming mechanism. When the dispersing
`medium water evaporates, the latex particles
`initially arrange themselves in the closest
`sphere packing. As drying continues, they
`flow together, provided the polymer sub-
`stance is soft enough. 'lhis process is termed
`coalescence. At this stage, the remaining
`water is squeezed out and a water-insoluble,
`practically homogeneous film is formed.
`The driving force for film formation is the
`gain in surface energy [1211, but in the case of
`these minute spherical latex particles, the
`capillary pressure which develops on evapo-
`ration of the water apparently plays a more
`important role [67]. According to Laplace
`this capillary pressure is
`
`P = 2y/r
`where y is the interfacial tension between
`water and air, and r the radius of the particles
`[122] or the radius of curvature of the con-
`cave meniscus [123] (Figure 4-2). If the
`radius of the dispersed particles is reduced by
`one order of magnitude, e.g. from 1 f..tm =
`1000 nm to 100 nm, the capillary pressure
`rises tenfold. This means that the most finely
`divided dispersions produce the best films.
`
`KASHIV1052
`IPR of Patent No. 9,492,392
`
`

`

`Coating Processes
`
`87
`
`composition applied from organic solution.
`Table 8- 2
`(p. 193)
`shows comparative
`measurements performed in 1982 by List [71,
`84], who attributes this effect to the signifi-
`cantly higher density of the latex films. This in
`turn can be explained by the capillary pres-
`sure effective during film formation. In prac-
`tical use it has been found that less film is re-
`quired in latex processing, e.g. for producing
`pellets of chlorphenamine maleate with a sus-
`tained-release coating of Eudragit'lli RS (see
`Figure 4- 4). Owing to the higher solids con-
`tent of latex formulations, fewer individual
`layers are normally necessary. If the polymer
`is not evenly distributed in the spraying
`process, more latex may, however, be re-
`quired to obtain the desired controlled-re-
`lease effect.
`With soft polymers and a processing
`temperature approx. 20 uc above the MFT,
`film formation from latexes is observed
`within a few seconds to minutes. However, if
`the polymers arc hard and the processing
`temperature close to the MFT, it may take
`several hours or even days. Electron micro-
`graphs reveal honeycomb structures in this
`case [59] as it can also be seen in Figure 4- Sa.
`Subsequent treatment of the films ("curing")
`for one to three hours at 60- 70 cc has been
`suggested for EC latexes to assure stable film
`properties [114]. Curing of coated pellets im-
`mediately after the coating process was found
`to have a significant influence on the drug re-
`lease profile [138]. Both retardation and en-
`hancement were observed to varying degrees,
`depending on the type of drug and the curing
`conditions in the range of 40 to 60 oc and 1 to
`24 hours. In the case of soft polymethacrylate
`latexes with an MFT below 10 oc, film forma-
`tion may be completed a few minutes after
`application of the coating formulation (see
`Figure 4- 5 b) [141]. In many cases, water-
`tight film coats already form isolating layers
`during spraying, so that the cores are immedi-
`ately sealed against penetration of the dis-
`persing medium water for the remainder of
`the process. Therefore it is often possible to
`
`a
`
`b
`
`Fig. 4-2. Film formation from latex particles
`(a) Deformation of the sphere during viscous flow ac-
`cording to Frenkel [121]
`(b) Action of the capillary forces according to Brown
`[123]
`r = particle radius
`El = half coalescence angle
`
`Film formation is disturhed if water is
`quickly soaked up by a porous surface. This
`reduces the time span for the capillary pres-
`sure required for coalescence of the particles
`to develop and therefore disturbs the film-
`forming process. The closer
`the drying
`temperature gets to the MFT, the more pro-
`nounced this effect is. If the latex particles
`have formed the closest sphere packing just
`before film formation, the water content of
`the layer, which corresponds to the intersti-
`tial volume, is only 26%. Therefore, there is
`less shrinkage during film formation from
`polymer dispersions than from polymer solu-
`tions.
`Given skilful processing, films from latex
`systems are practically pore-free and may
`even be less permeable than films of the same
`
`KASHIV1052
`IPR of Patent No. 9,492,392
`
`