ISSN 1157 — 1497
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`S.T.P.PHARMASCIENCES—SEPTEMBRE-OCTOBRE1996—6(5)317-380
`
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`NOV 6 1996
`
`Purdue 2037
`Collegium v. Purdue, PGR2018-00048
`
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`Purdue 2037
`Collegium v. Purdue, PGR2018-00048
`
`

`

`S.T.P. PHARMA SCIENCES 6 (5) 317-319 1996
`
`STP PHARMA SCIENCES
`
`Journal scientifique de/Scientific journal of
`
`Societe fran9aise des sciences et techniques pharmaceutiques, SFSTP, 5, rue Basse-des-Carmes, 75005 Paris, France
`President Henri Delonca
`Association de pharmacie galenique industrielle, APGI, rue Jean-Baptiste-Clement, 92290 Chatenay-Malabry, France
`President Dominique Duchene
`
`Coordinateur scientifique/Scientific coordinator
`Dominique Duchene, Faculte de Pharmacie, Universite de Paris-Sud, rue Jean-Baptiste-Clement, 92290 Chatenay-Malabry, France
`
`Redacteur en chef pour I' Amerique du Nord/Editor in chief for North America
`Joseph R. Robinson, School of Pharmacy, University of Wisconsin , 425 North Charter Street, Madison, Wisconsin 53706, United States
`
`Redacteur en chef pour le Japan/Editor in chief for Japan
`Tsuneji Nagai, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142, Japan
`
`Di recteur de la publication/Publications director
`Dominique Dupont, Editions de Sante, 49, rue Galilee, 75116 Paris, France
`
`Conseil scientifique/Editoria/ board
`
`Simon Benita, The Hebrew University of Jerusalem, Israel
`Pierre Buri, Universite de Geneve, Switzerland
`Carla Caramella, Universita di Pavia, Italy
`Vie W. Chien, Rutgers, The State University of New Jersey,
`, Piscataway, United States
`Patrick Couvreur, Universite de Paris-Sud, Chatenay-Malabry, France
`Patrick P. Deluca, University of Kentucky, Lexington, United States
`Michael Dittgen, VED Jenapharm GmbH , Jena, Germany
`Alexander T. Florence, London University, United Kingdom
`Christine Graffner, S6dertalje, Sweden
`1 A. Atilla Hmcal, Hacettepe University, Ankara, Turkey
`Hans E. Junginger, Leiden University, Netherlands
`Yoshiaki Kawashima, Gifu Pharmaceutical University, Japan
`J6rg Kreuter, Frankfurt Universitat, Germany
`
`Hans Leuenberger, Basel Universitat, Switzerland
`James W. McGinity, The University of Texas at Austin, United States
`Marcelo Nabucchio, Buenos Aires, Argentina
`Nicholas A. Peppas, Purdue University, West Lafayette, United States
`Nicolas Plate, Moscow, Russia
`Francis Puisieux, Universite de Paris-Sud , Chatenay-Malabry, France
`Marco Fabrizio Saettone, Universita di Pisa, Italy
`Jelka Smid-Korbar, Ljubljana, Slovenia
`Eva Smolkova-Keulemansova, Charles University, Praha,
`Czech Republic
`Jose L. Vila Jato, Universidad de Santiago de Compostela, Spain
`Lucy S.C. Wan, University of Singapore, Singapore
`Clive G. Wilson, University of Strathclyde, Glasgow, United Kingdom
`
`Objectifs
`
`Scope
`
`STP Pharma Sciences paralt tousles deux mois (six numeros
`J par an). Ce journal publie des articles originaux soit en langue
`fran9aise, soit en langue anglaise . Ces articles sont soumis a
`i
`!'appreciation de deux referes internationaux. La preference est
`don nee aux articles de recherche se rapportant a des travaux de
`recherche originaux et recents. Le numero de janvier-fevrier est
`un numero thematique auquel certains auteurs sont invites a
`participer. Le numero de juillet-aoOt comporte un article de revue
`exhaustive demande a un specialiste de renom international.
`
`STP Pharma Sciences will be published bi-monthly (six issues
`per year). This journal will publish original articles either in
`French or in English. These articles will be submitted for
`assessment to two international referees. Preference will be
`given to research articles concerning original, recent research
`work. The January-February number will be a thematic issue to
`which certain authors will be invited to contribute. The July(cid:173)
`August number will contain an exhaustive review article
`requested from a specialist of international renown.
`
`Indexation
`
`Abstract
`
`STP Pharma Sciences est indexe dans Chemical Abstracts,
`Current Contents/Life Sciences, International Pharmaceutical
`Abstracts, Pascal.
`
`STP Pharma Sciences is abstracted or indexed in Chemical
`Abstracts, Current Contents/Life Sciences, International
`Pharmaceutical Abstracts, Pascal.
`
`317
`
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`

`

`S.T.P. PHARMA SCIENCES 6 (5) 365-369 1996
`
`Influence of melting point and hydrophilic/lipophilic
`balance on the release of salbutamol sulfate
`from lipid matrices
`
`A. Esquisabel, A. San Vicente, M. Igartua, R.M. Hernandez,
`A.R. Gascon, M.B. Calvo and J.L. Pedraz*
`
`Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy,
`University of the Basque Country (UPVIEHU), Marques de Urquijo sin, 01006 Vitoria-Gasteiz, Spain
`*Correspondence
`
`Salbutamol is a drug with a short elimination half life, and
`is thus a possible candidate for the development of sustained
`release formulations. We developed sustained release lipid
`matrices using Gelucires. Three different release profiles were
`observed: fast release, in the case of Gelucires 33/01, 35/10,
`) of
`37/02, 42/12 and 44/14, with a mean dissolution time (Td50
`6, 16, 3, 40 and 12 min ; a sustained release for Gelucires
`48/09, 50/13 and 53/10 with a mean dissolution time of 186, 147
`and 168 min; and a slow releaseforGelucires46/07 and 50/02,
`with a mean dissolution time of 310 and 621 min, respectively.
`The percentages of salbutamol released with Gelucires 46/07
`and 50/02 were below 60% of the dose. Multiple regression
`analysis of the hydrophilic/lipophilic balance ( HLB ), melting
`point (MP), dissolution constant (K) and mean dissolution
`) yielded the following equations: K, = 3.13 -
`time (Tel50
`0.262 *HLB - 0.0648':'MP + 0.00556 HLB*MP, (R 2 =0. 88), and
`Tel50 = - 1485 + 105*HLB + 43.2*MP- 3.03 HLB *MP, (R 2 =
`0.91).
`
`Le salbutamol est un principe act if presentant une demi-vie
`d'elimination breve, ce quijustifie son incorporation dans des
`formes a liberation prolongee. Les auteurs ont mis au point des
`matrices lipidiques a liberation prolongee a base de Gelucire.
`Trois profils de liberation ont ete obtenus : une liberation
`rapide clans le cas des Gelucires 33/01, 35/10, 37102, 42/12 et
`) de
`44/14, avec des temps de dissolution moyens (Td50
`respectivement6, 16, 3, 40et 12 min, une liberation rapideavec
`Les Gelucires 48/09, 50/13 et 53/10 avec des Tel50 de
`respectivement 186, 147 et 168 min, et une liberation Lente avec
`Les Gelucires 46/07 et 50/02 avec des Tel50 de respectivement
`310 et 612 min. Les pourcentages de liberation du salbutamol
`a partir des Gelucires 46/07 et 50/02 ont ete inferieurs a 60%
`de la dose. L'analyse en regression multiple de la balance
`hydrophile/lipophile (HLB), du point de fusion (MP), de la
`constante de dissolution (Kl) et du temps de dissolution moyen
`(Td50)aconduitaux equations suivantes: Kl= 3,13-0,262*HLB
`- 0,0648*MP + 0,00556*HLB*MP(R2 = 0,88) etTd50 = -1485
`+ 105*HLB - 43,2*MP - 3,03 HLB *MP (R 2 = 0,91).
`
`Key words : Gelucire - Salbutamol - Sustained release -
`Capsules - Hydrophilic/lipophilic balance - Melting point -
`Release kinetics.
`
`Mots clefs: Gelucire -Salbutamol - Liberationprolongee -
`Capsules - Balance hydrophilellipophile - Point de fusion -
`Cinetiques de liberation.
`
`Salbutamol is a potent adrenergic agonist eliminated from
`the body through biotransformation with predominatly ~2
`activity and minimal ~ 1 activity, thus providing bronchodilation
`with little myocardial stimulation. As a result, it is widely used
`for the treatment of asthma in adults and children [ 1, 2]. Since
`the half life of orally administered salbutamol is approximately
`5 h, the drug must be dosed three to four times daily to maintain
`bronchodilation, thus becoming a possible candidate for the
`development of controlled or sustained release formulations
`[3]. There is an increasing interest in the simplification of drug
`dosage schedules, mainly in terms of reducing dosing frequency,
`Which is particularly important during the treatment of chronic
`diseases. It has been demonstrated that whe n dru gs are
`administered less frequently, patient compliance to the treatment
`is improved [ 4] .
`
`Many approaches have been used to achieve controlled
`release or sustained release formulations of salbutamol. These
`formulations include hydrophilic matrices, pellets, osmotic
`pumps and microcapsules [5-7]. Another approach that is
`widely used to obtain sustained release formulations for different
`drugs consists in the use oflipid matrices (8-11]. Lipid matrices
`are simple and rapid to produce cost relatively little, and , in
`some cases, it is possible to achieve minimum influence from
`the physiological variables. Matrices can have different shapes,
`i.e., film, disc, cylinder, tablet, microparticle or capsule, and are
`potentially suitable for common administration routes [ 12].
`
`Recent studies have reported the use of Gelucires as
`excipients to prepare susta ined release lipid matrice s
`(9, 10, 11 , 13, 14] . Gelucire excipients are saturated
`
`365
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`

`S.T.P. PHARMA SCIENCES 6 (5) 365-369 1996
`
`polyglycolized glycerides. They are well defined mixtures of
`mono-, di- and triglycerides and mono- and diesters of
`polyethyleneglycols, and are produced by using
`polyethyleneglycols of a molecular weight situated between
`200 and 2000, either for partial glycolysis of hydrogenated
`vegetable oils or for esterification of saturated fatty acids [ 12].
`Gelucires are identified by their melting point (ranging from
`33 to 65°C) and hydrophilic/lipophilic balance (ranging from 1
`to 14). Though they have been used to encapsulate liquid or
`semisolid drugs, they can also be employed to achieve sustained
`release of active ingredients from tablets, granulates or hard
`gelatin capsules [9].
`
`The aim of the present work was to evaluate the influence
`of the Gelucire melting point and hydrophilic/lipophilic balance
`values as factors that may condition the release of salbutamol
`sulfate from formulations using Gelucires as lipid excipients.
`
`I. MATERIALS AND METHODS
`
`1. Materials
`
`Salbutamol sulfate (USP XXII) was supplied by Vencaser
`SA (Bilbao, Spain). 1.2 mg of salbutamol sulfate is equivalent
`to 1 mg of salbutamol. Gelucires were supplied by Gattefosse
`Espana (Madrid, Spain). All other chemicals were of analytical
`grade.
`
`2. Formulations
`
`Lipid matrices were prepared by a melting process. Next,
`hard gelatine capsules (size No. 4) were filled with salbutamol
`sulfate and different Gelucires: 33/01, 35/10, 37/02, 42/12,
`44/14, 46/07, 48/09, 50/02, 50/13, 53/10.
`
`Gelucire was melted in a thermostatic bath at a temperature
`10°C above its melting point. The active substance was
`incorporated by stirring until a dispersion was obtained.
`Afterwards, the capsules were filled with the mixture and
`cooled.
`
`3. Control of capsulfs
`
`The theoretical weight of the capsules ranged from 236 to
`267 mg, depending on the type of Gelucire used. Following the
`USP XXII procedure [16], twenty capsules were weighed
`individually and their average weight was determined. The
`requirements were met if each of the individual weights was
`within the limits of90 to 110% of the average weight. However,
`in order to obtain more homogeneous batches, we used narrower
`limits (95-105%) .
`
`A sample of thirty capsules was selected and ten of them
`were assayed for content uniformity. The requirements were
`met if the content of each of not less than nine of the capsules
`fell within the limits of 85 to 115% of the average of the limits
`specified in the potency definition in the monograph, and if the
`content of none of the capsules fell outside the limits of 75 to
`
`Influence of melting point and hydrophilic/lipophilic balance
`on thq release of salbutamol sulfate from lipid matrices
`A. Esquisabel, A. San Vincente, M. Igartua, R.M. Hernandez,
`A.R. Gascon, M.B. Calvo and J.L. Pedraz
`
`125% of that average. The amount of salbutamol sulfate in the
`capsules was within the range of 9.50 to 9.71 mg, which is
`equivalent to 7.92 to 8.09 mg of salbutamol.
`
`4. Dissolution tests
`
`Dissolution tests (six replicates, one capsule per vessel)
`were performed using a USP XXII type II apparatus [ 16] in
`deionized water (1000 ml), at 100 r/min and 37 ± 0.5°C.
`Samples of 5 ml were withdrawn at fixed time intervals, filtered
`through a 0.45 µm filter (Millipore) and replaced with the same
`volume of dissolution medium. The dilution caused by this
`addition was corrected when the amount of drug released into
`the medium was calculated. The dissolved amount of drug each
`time was expressed as percentage of the dose.
`
`The concentration of salbutamol was determined by a
`spectrofluorometric method using a Kontron SFM 25 apparatus
`at the 220 nm ( excitation) and 309 nm ( emission) wavelengths.
`Gelucire excipients were tested for fluorescence emission at
`these wavelengths, and no interference with salbutamol
`determination was experienced. The relationship between
`fluorescence and concentration of salbutamol was found to be
`linear between 0.1 and 10 µg/ml, with correlation coefficients
`above 0.99.
`
`5. Data analysis
`
`In order to understand the mechanism of drug release from
`these matrices, dissolution curves were fitted according to the
`non-linear equation[l 7] :
`
`M/M =K t11
`=
`
`t
`
`Eq.1
`
`where M/M= is the fraction of drug released up to time t, K is
`a constant incorporating the structural and geometric
`characteristics of the release device, and n is the release
`exponent indicative of the release mechanism.
`
`The influence of Gelucire characteristics on the release of
`salbutamol was evaluated in terms of the parameters calculated
`by Gompertz's equation [18] :
`
`Q=Q
`max
`
`.e(-~.e-K1t)
`
`Eq.2
`
`where Q is the amount of dissolved drug, Q
`is the total
`max
`amount of drug in the capsule, K1 is the first order rate
`dissolution constant, and~ characterizes the sigmoidicity factor.
`
`Td50
`, the time required to dissolve 50% of the active
`substance, can be deduced from the formula :
`
`Td50 = (0.367 + In ~)/K 1
`
`Eq.3
`
`The curve was fitted with Nonlin 86, a non-linear regression
`analysis program [19]. The program is based on the Nelder(cid:173)
`Mead algorithm and run on a PC. The goodness of fit was
`evaluated on the basis of the weighted squared residuals,
`
`366
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`Purdue 2037
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`
`

`

`Influence of melting point and hydrophilic/lipophilic balance
`on the release of salbutamol sulfate from lipid matrices
`A. Esquisabel, A. San Vincente, M. Igartua, R.M. Hernandez,
`A.R. Gascon, M.B. Calvo and J.L. Pedraz
`
`Akaike's information criterion values, R-squared, and the
`correlation coefficient [20].
`
`II. RESULTS AND DISCUSSION
`
`1. Release kinetics
`
`Figure 1 presents the release of salbutamol sulfate from
`hard gelatin capsules containing different Gelucires. The release
`profiles were dependent on the type of Gelucire. Gelucires
`33/01, 35/10, 37 /02, 42/12 and44/14release salbutamol rapidly
`from the matrix. In contrast, Gelucires 48/09, 50/13 and 53/10
`showed a higher efficiency in sustaining the release of salbutamol
`from the lipid matrix ; the slowest release was obtained for
`Gelucires 46/07 and 50/02. The kinetic parameters obtained
`from the non-linear equation are shown in table 1.
`
`120.00
`
`-
`
`-
`
`•
`
`JJ,'()J
`
`r---JS! IU
`
`- · •
`
`.l7/02
`
`.... <.>
`
`···- 4l/J2
`
`.t..
`
`-
`
`44114
`
`0
`
`JOO
`
`200
`
`300
`
`400
`
`500
`
`600
`
`-Y··
`
`53110
`
`time (min)
`
`Figure 1 - Release of salbutamol from hard gelatin capsules formulated
`with different Gelucires.
`
`Table I - Kinetic parameters of salbutamol release from Gelucire
`matrices obtained from a non-linear equation.
`
`Hydrophilic/
`lipophilic balance
`
`Melting
`point
`
`K (%min-")
`
`n
`
`1
`10
`2
`12
`14
`7
`9
`2
`13
`10
`
`33
`35
`37
`42
`44
`46
`48
`50
`50
`53
`
`24.07
`9.52
`26.02
`1.65
`16.50
`0.48
`1.30
`0.18
`1.85
`1.45
`
`0.47
`0.61
`0.68
`0.89
`0.45
`0.81
`0.70
`0.96
`0.68
`0.69
`
`The n values obtained for the Gelucires with a fast release
`of salbutamol sulfate from the lipid matrix, i.e., 33/01, 35/10,
`37/02, 42/12 and44/14, ranged from 0.45 to 0.89, demonstrating
`that diffusion processes and anomalous transport mechanisms
`do exist [ I 4]. The fast release of salbutamol from these
`formulations is indicated by the high values of the dissolution
`constant, K, from 1.65 % miff11 in capsules containing Gelucire
`42/12 to 26.02% min·" in capsules with Gelucire 37/02 .
`According to Ratsimbazafy and Brossard [ 15], these Gelucires
`
`S.T.P. PHARMA SCIENCES 6 (5) 365-369 1996
`
`show a high degree of deformation or disintegration after 1 h in
`simulated gastric juice at 37°C, with a mass that either spreads
`on the surface or softens. This fast release could be due to a fast
`solubilization and disintegration of the Gelucires in the
`dissolution media eased by their low melting point [21].
`Therefore, these Gelucires cannot be used to achieve sustained
`release of salbutamol sulfate from capsules.
`
`A second group of Gelucires, 48/09, 50/13 and 53/10,
`showed a slower release rate. All of them have melting points
`above 48°C and hydrophilic/lipophilic balance values above 9.
`Mathis and Heimendinger [22] studied the release profiles of
`salicylic acid from Gelucires 37/02, 50/02, 62/05, 48/09 and
`44/14, observing that when the melting point of the excipient
`increased, drug release was slower. The values obtained for the
`n exponent were near 0.7, indicating the existence of an
`anomalous (non-Fickian) transport mechanism. Several authors
`[21 , 23] found that Gelucire 48/09 exhibits an inert mass which
`remains intact but softens after 1 h in simulated gastric juice.
`Gelucires 50/13 and 53/10 may suffer solubilization and
`disintegration, but they remain intact in an aqueous medium ;
`however, they soften and become plastic after 1 h in gastric
`juice. The release mechanism from these Gelucires may be due
`to a hydration with gelation and the subsequent diffusion of the
`drug from the resu I tant mass [24]. The dissolution rate constants
`ranged from 1.30 to 1.85% miff", allowing a complete release
`of salbutamol in 8 to 10 h. Consequently, these formulations
`can be considered valid to achieve a sustained release of
`salbutamol.
`
`Gelucire 46/07 and 50/02 had slower dissolution rates. This
`may be considered time independent for Gelucire 50/02, since
`then exponent value obtained from the non-linear equation is
`nearly 1. These Gelucires are characterized by high melting
`points and low hydrophilic/lipophilic balance values. Gelucire
`46/07 is an inert mass in an aqueous medium, but in simulated
`gastric juice at 37°C and after 1 hit takes the form of an entire
`mass which floats in the medium [15]. Gelucire 50/02 may
`suffer solubi lization, but it remains intact. However, it softens
`after 1 h at 37°C. The release mechanism from these Gelucires
`could be explained by an erosion of the Gelucire 46/07 inert
`mass and the slow solubi lization of the Gelucire 50/02 [24, 25].
`The value of the dissolution constant was 0.48 % min·11 for
`Gelucire 46/07, decreasing to 0.18 % miff" for Gelucire 50/02.
`The dissolved salbutamol percentages at 10 h were below 60%
`of the dose in both cases.
`
`2. Influence of hydrophilic/lipophilic
`balance and melting point
`
`The aqueous behaviour of the different Gelucires and
`several studies on the influence of the melting point and
`hydrophilic/lipophilic balance of Gelucires on the release of
`drugs have shown that there is a simultaneous influence of these
`two factors [9]. Our study investigated the simultaneous
`influence of the Gelucire melting point and
`the
`hydrophilic/lipophilic balance on the two dissolution parameters
`obtained from Gompertz' s equation : the first order dissolution
`
`367
`
`Purdue 2037
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`
`

`

`S.T.P. PHARMA SCIENCES 6 (5) 365-369 1996
`
`Influence of melting point and hydrophilic/lipophilic balance
`on the release of salbutamol sulfate from lipid matrices
`A. Esquisabel, A. San Vincente, M. Igartua, R.M. Hernandez,
`A.R. Gascon, M.B. Calvo and J.L. Pedraz
`
`constant of (K) and the mean dissolution time (Td50). The
`kinetic parameter values corresponding to Gompertz' s equation
`are listed in table II.
`
`Table II - Kinetic parameters of salbutamol release from Gelucire
`matrices obtained from the Gompertz equation.
`
`Hydrophilic/
`lipophilic balance
`
`Melting
`point
`
`~
`
`K (%/min)
`
`Td 50 (min
`
`1
`10
`2
`12
`14
`7
`9
`2
`13
`10
`
`33
`35
`37
`42
`44
`46
`48
`50
`50
`53
`
`1016.90
`2.18
`3.48
`3.89
`28.45
`2.71
`2.80
`4.32
`2.61
`2.35
`
`0.96
`0.07
`0.61
`0.043
`0.303
`0.0044
`0.0075
`0.0029
`0.0091
`0.0072
`
`5.58
`16.38
`2.66
`39.95
`11.67
`309.92
`185.94
`621 .33
`147.41
`168.20
`
`These results show that in capsules containing fast releasing
`Gelucire, i.e., 33/01, 35/10, 37/02, 42/12 and 44/14, the
`, were found to range from 0.96
`dissolution constant values, K 1
`, which corroborating the obtained mean
`to 0.043 min-1
`dissolution time values of less than 40 min. As deduced from
`the results obtained from the use of the non-linear equation,
`these Gelucires cannot be used to modulate the release of
`salbutamol sulfate from hard gelatine capsules. The dissolution
`constant values obtained for the Gelucires that provide a
`sustained release of salbutamol, i.e., 48/09, 50/13 and 53/10,
`were 0.0075 %/min for Gelucire 48/09, 0.0091 %/min for
`Gelucire 50/13, and 0.0072 %/min for Gelucire 53/10, yielding
`mean dissolution time values of 185.94, 147.41 and 168.20 min
`for Gelucires 48/09, 50/13 and 53/10, respectively. In the case
`of the Gelucires that showed the slowest salbutamol release,
`i.e., 46/07 and 50/02, these values were 0.0044 %/min and
`0.0029 %/min, respectively, for the dissolution constant K 1
`•
`The mean dissolution time values were 309.92 min in the case
`of Gelucire 46/07 and 621.33 min for Gelucire 50/02.
`
`The influence of the Gelucire parameters, melting point and
`hydrophilic/lipophilic balance, on the release of salbutamol
`was evaluated in terms of the dissolution constant K 1 and mean
`. The first order dissolution rate constant
`dissolution time Td50
`) was dependent on the hydrophilic/lipophilic balance (HLB ),
`(K 1
`the melting point (MP), and the corresponding cross term effect
`according to equation 4 :
`
`Kl = 3.13 - 0.262 HLB - 0.0648 MP+
`0.00556 HLB*MP, R2 = 0.88
`
`Eq.4
`
`An increase in the dissolution constant was observed for
`low melting point values when the hydrophilic/lipophilic balance
`decreased. However, in the case of high values of melting
`points, the dissolution constant value decreased when the
`hydrophilic/lipophilic balance decreased (figure 2).
`
`The mean dissolution time (Td50
`) was found to be dependent
`on these parameters according to the following equation obtained
`by multiple regression analysis :
`
`HLB
`
`13
`
`MP
`
`Figure 2 - Influence of hydrophilic/lipophilic balance (HLB) and melting
`point (MP) on the first order constant of dissolution (K,) .
`
`Td50 = - 1485 + 105 HLB + 43.2 MP -
`3.03 HLB*MP, R2= 0.91
`
`Eq. 5
`
`A significant increase in the mean dissolution time value
`was achieved by increasing the melting point and decreasing
`the hydrophilic/lipophilic balance, as figure 3 shows. This
`shows
`that high melting point values and
`low
`hydrophilic/lipophilic balance values can allow a sustained
`release of salbutamol sulfate from capsules containing Gelucires
`as excipients to be obtained.
`
`Td50
`
`800
`700 -
`600
`500
`400 /
`300
`200
`100
`0
`-100
`
`Figure 3 - Influence of hydrophilic/lipophilic balance (HLB) and melting
`point (MP) on the mean dissolution time (Td 50
`).
`
`MP
`
`*
`
`*
`
`The results obtained show that there is a considerable range
`of Gelucires with hydrophilic lipophilic balance values from 9
`to 13 and melting points from 48 to 53, and that they are
`candidates for salbutamol sulfate sustained release formulations.
`These Gelucires allow the complete dose to be released in an 8-
`10 h period. The average dissolution time ranges from 2.5 to
`3.1 h.
`
`368
`
`Purdue 2037
`Collegium v. Purdue, PGR2018-00048
`
`

`

`Influence of melting point and hydrophilic/lipophilic balance
`on the release of salbutamol sulfate from lipid matrices
`A. Esquisabel, A. San Vincente, M. Igartua, R.M. Hernandez,
`A.R. Gascon, M.B. Calvo and J.L. Pedraz
`
`We have shown that there is a simultaneous influence of the
`melting point and the hydrophilic lipophilic balance on the
`dissolution parameters obtained from Gompertz's equation in
`such a way that the high melting point values allow us to obtain
`a sustained release of salbutamol.
`
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`MANUSCRIPT
`
`Received 27 December 1995, accepted for publication 28 May 1996.
`
`369
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`Collegium v. Purdue, PGR2018-00048
`
`