Contenido en sustancia activa. Estabilidad de Medicamentos. Caracteristicas esenciales de calidad:

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1 de Medicamenos Conenido en susancia aciva Caracerisicas esenciales de calidad: Conenido en susancia aciva Forma farmacéuica y caraceres organolépicos Flora microbiana Toxicidad Biodisponibilidad Periodo de validez: reducción del % en susancia aciva Toxicidad no aumena debido a producos de degradación Fecha de caducidad: mes y año Periodo de validez máximo 5 años (RD 736/987 de 7 de marzo) Esables, seguros, eficaces Esudios de esabilidad Sobre la susancia aciva Fase de preformulación: Sólido y disolución Compaibilidad con excipienes frene a operaciones básicas Especialidad erminada Ensayos a largo plazo Ensayos de envejecimieno acelerado. Aleraciones de los medicamenos Inesabilidad Física Inesabilidad uímica Inesabilidad Microbiológica 3 4

2 Inesabilidad Física: aleración de las caracerisicas galénicas Inesabilidad química Consecuencias: Aspeco Regularidad de la dosificación Biodisponibilidad (caducidad biofarmacéuica) Vias degradación física: Polimorfismo Crecimieno crisalino Sedimenación Floculación Coalescencia Cinéica química Orden y molecularidad de la reacción 5 6 Sabiliy Calculaions Sabiliy Calculaions a ypical chemical reacion D W P D W P Reacion rae [D]*[W] D and W, "colliding" o form one or more produc molecules, he rae of reacion: proporional o he number of collisions a he number of collisions is proporional o he produc of he concenraions of he wo species: Reacion rae [D]*[W] Reacion rae corresponds o he rae of loss of D and is denoed (d[d]/d) d[d] α[d][w] d we le be he rae consan d[d] [D][W] d 7 8

3 Sabiliy Calculaions Order of reacion: sum of he exponens of he concenraion erms in he rae equaion d[d] [D][W] d Second order reacion Sabiliy Calculaions Order of reacion: d[d] [D][W] d If he waer concenraion W is held consan (by having a large excess, as in mos soluions) hen : d[d] [D] d where [W] and he reacion is apparen firs order or pseudo firs order 9 Sabiliy Calculaions Order of reacion: If, now, in addiion, we also fix he drug concenraion (e.g., by maing a suspension), he equaion becomes: d[d] d Orden Ecuación velocidad -dc/d -dc/d-*c Unidades C* - - where [D] [D][W] and he reacion is apparen zero order n -dc/d*c -dc/d*c*b -dc/d*c n C - * - C n- * - 3

4 Firs-Order Calculaions Orden Ecuación velocidad -dc/d -dc/d-*c -dc/d*c Ecuación inegrada C C C C e + C C Ln Concenraion [D] [D] e D P Firs order Time (min) Concenraion Firs order Time (min) T / 3 4 Firs-Order Calculaions The half-life, ½: is he ime for [D] o become [D]/, [D] ln ln ln[d].693 Firs-Order Calculaions The shelf-life, 9 : usually aen o be he ime for [D] o reach.9[d], ha is, % decomposiion,

5 Firs-Order Calculaions Example: aspirin (aceylsalicylic acid) a ph.5 he (pseudo-firs-order) rae consan is 5 x -7 s - a 5ºC. Zero-Order Calculaions rae equaion wih no concenraion dependence. d[d] d Inegraing from o wih [D] [D] a, half-life shelf life x s -7 5 x.5 5 x 5 9. x s -7 [D] [D] [D] - * d[d] [D] d 7 8 Zero-Order Calculaions [D] [D] - * Half life Shelf-life.5[D] 9.[D] Zero-Order Calculaions D] [D] - * Zero order Concenraion Time mins 9.5[D] 5

6 Zero-Order Calculaions Example: aspirin (aceylsalicylic acid) a ph.5 he (pseudo-firs-order) rae consan is 5 x -7 s - a 5ºC. Aspirin solubiliy.33 g/ ml. for an aspirin suspension: zero-order rae TEMPERATURE EFFECTS Acivaion Energy Calculaions Reacion raes are proporional o he number of collisions per uni ime. he number of collisions increases as he emperaure increases. 5 x -7 s - x.33 g/ ml.65 x -7 g/(ml * s) The reacion rae consan is observed o have an exponenial dependence on emperaure described by he Arrhenius equaion Dose of aspirin: 65 mg/easpoon(5 ml) 3 g/ ml. shelf life (.)(3).65 x x s9 days A exp(-ea/rt) :reacion rae consan A :consan Ea: acivaion energy of he chemical reacion T : he absolue emperaure ( ºC ºC). log log A - Ea/.33RT TEMPERATURE EFFECTS 6 TEMPERATURE EFFECTS Typical Arrhenius plo of log agains /T, Energy Kcal/mol A+B reacans Eac Kcal/mol B+C producs Log K (/T(Kº))* Exen of reacion Slope 3.5* 3 Ea 3.5* 3 *(.33)*(.987)6. Kcal/mol 3 4 6

7 TEMPERATURE EFFECTS Compound Reacion E a (cal/mol) Ascorbic Acid Oxidaion 3 Aspirin Hydrolysis 4 Aropine Hydrolysis 4 Benzocaine Hydrolysis 9 Chloramphenicol Hydrolysis Epinephrine Oxidaion 3 Procaine Hydrolysis 4 Thiamine Hydrolysis Acivaion Energies for Some Drug Decomposiion Reacions 5 TEMPERATURE EFFECTS Example: Sulfaceamide. firs-order rae consan in he ph-independen region (5-) K 9 x -6 s - a ºC. Ea.9 cal/mol a ph 7.4. Calculae he shelf life a 5ºC. 5 9 E a log log.33r T T (.3)(.987) x 5 (8.7 x -5 ) (9 x -6 s - ) 7.85 x - s x s x s 4.5 years TEMPERATURE EFFECTS Example The following rae consans were deermined for 5-fluorouracil decomposiion a ph 9.9. (a) (b) (ºC) 6 (s - ) Deermine he acivaion energy a his ph; Exrapolae he graph o room emperaure (5ºC) and deermine he rae consan and shelf life a his emperaure. TEMPERATURE EFFECTS Answer: (a) from he Arrhenius plo of he daa we obain The slope B -.3Ea/R Ea 4.5 cal/mol Log /T (Kº) 7 8 7

8 TEMPERATURE EFFECTS (b) From exrapolaion of he graph o 5ºC (/T.335), we obain log 5ºC ºC.38 x -9 s x 7 s.4 years -Value Calculaions: Consider he raio of rae consans T/Tl a wo emperaures T and T. Consider TT+º Log /T (Kº) The quaniy is defined as (T+ ) T The facor can be calculaed from he nex equaion: + E exp R T T (T ) a T + Noe ha Ea is always posiive Value Calculaions: The acivaion energies for drug decomposiions usually fall in he range o 4 cal/mol. Nex able gives values of Ea corresponding o hree rounded values of. These values of, 3, or 4 o represen low, average, and high esimaes of when Ea is unnown (3 o ºC) E a (cal/mol) -Value Calculaions: For an arbirary change in emperaure, ΔT T - T, Δ (T+ΔT) ( ΔT/) T T 3 3 8

9 -Value Calculaions: For an arbirary change in emperaure, ΔT T - T, E ΔT a ΔT exp R (T +Δ T)(T) Muliplying he exponenial erm by T + i T + -Value Calculaions: E Δ T (T + ) + +Δ a Δ T exp R (T )(T) (T T) Ea exp R (T + )(T) Δ + +Δ [ T /][(T ) /(T T)] Δ T [ Δ T /][(T+ ) /(T+ΔT)] This equaion is exac. However, since T 3K, (T + )/(T + T), gives E Δ T (T + ) a Δ T exp R (R +Δ T)(T) (T + ) Δ (T+ΔT) ΔT/ T T Value Calculaions: Example Calculae he facors by which rae consans may change for: (a) a 5 o 5ºC emperaure change (b) a 5 o ºC emperaure change. Answer: (a) ΔT +5, + (5+ 5) (5/) , 5.6, 3 for, 3, 4, respecively -Value Calculaions: (b) a 5 o ºC emperaure change. Answer: ΔT -5, ( 5) ( 5/) 5 /5.7, /5.6, /3 for, 3, 4, respecively Thus he rae decreases o beween /6 and /3 of he iniial rae. Thus he rae increases beween 6-fold and 3-fold, wih a probable average increase of abou 6-fold

10 -Value Calculaions: 4 provides he larges esimae for he increase in rae wih increasing emperaure, provides he smalles reasonable esimae for he decrease wih decreasing emperaure. The expiraion dae is given for room emperaure. Wha is he expeced exension of he shelf life in a refrigeraor? Example: Using, 3, 4, calculae he half-life change from 7ºC o 5ºC for mehyl paraben a ph 4. We have ΔT , -45 /3, () -45 /4, (3) -45 /5, (4) Since 7ºC.6 x -6 s- (from he monograph) hen ½ (7ºC) 4.3 x 7 s 5 days ½ (5ºC) 3 yr ( ) 99 yr ( 3) 79 yr ( 4). The expiraion dae is given for refrigeraion condiions. How long may he produc be lef a room emperaure? The expiraion dae is for room-emperaure condiions, and i is desired o hea he produc in serilizaion. Wha percen decomposiion can be expeced a he higher emperaure? The expiraion dae is for room-emperaure condiions, and i is desired o hea he produc in serilizaion. Wha percen decomposiion can be expeced a he higher emperaure? Problems of his ype require esimaes of he effec of emperaure on he shelf life. Assuming we do no have exac Ea values available, we use he values of, 3, and 4 o mae such esimaes. Zero order Firs order 9 9.[D ].5 (T) 9 a (T +Δ T) 39 4

11 (T ) 9 ( T/) Ti Δ or, since 9 (T) a/ T : (T ) 9 9 ( T/) Δ a (T) he esimae of 9(T) is independen of he order. a posiive ΔT (T > T) reduces he shelf life, a negaive ΔT(T < T) increases i. Example A. The expiraion period for a reconsiued produc is 8 h a room emperaure. Esimae he expiraion period when he produc is sored in he refrigeraor. ΔT -ºC, (T ) (T) 9 9 ( T/) Δ 9 ( /) 9 (5ºC) 8 * 7 h ( ) 8 *3 6 h ( 3) 8 * 4 88 h ( 4) (5º) conservaive esimae would be 7 h and a liely esimae 6 h Example B. A newly reconsiued produc is labeled o be sable for 4 h in a refrigeraor. Wha is he esimaed shelf life a room emperaure? 9 (5ºC) 4 h (T ) (T) (5º ) 9 9 ( T/) Δ 9 (/) 9 (5ºC) 4/4 6 h ( ) 4/9.7 h ( 3) 4/6.5 h ( 4) Thus a liely value is abou 3 h, wih a conservaive esimae of.5 h and a possible value of 6 h. 4 If he produc has been sored for a nown lengh of ime a anoher emperaure:. compue he ime inerval a he specified emperaure ha would give he equivalen decomposiion o ha which occurred a he acual sorage emperaure and. subrac his value from or add i o he label dae for a new expiraion dae

12 Example The expiraion dae for a produc is one year from he curren dae when sored in a refrigeraor. The produc has been sored-for one monh a room emperaure. If he produc is now reurned o he refrigeraor, wha is he new expiraion dae? Answer One monh a room emperaure would be equivalen o (T) (T ) (T ) 9 ( ΔT/) 9 ( ΔT/) 9 * 4 monhs ( ) *3 9 monhs ( 3) *4 6 monhs ( 4) ha is, 4, 9, or 6 monhs a 5ºC. The mos liely esimae is 9 monhs, hence if he produc is reurned o he refrigeraor, only 3 monhs would be lef. Example. The ampicillin monograph in he Physicians' Des Reference () saes ha he reconsiued suspension is sable for 4 days in a refrigeraor. If he produc is lef a room emperaure for h, wha is he reducion in he expiraion period? (T) (T) (T) 9 ( ΔT/) 9 ( ΔT/) 9.5 * days ( ).5 * days ( 3).5 * 4 8 days ( 4) The expeced reducion is hus 4.5 days Influencia del ph Influencia del ph Example Example:pH-Rae profile for he dehydraion of srepoviacin A a 7 C ph-rae profile for hydrolysis of ciric acid anhydride a 5 C 47 48

13 D. ph EFFECTS (). Sigmoid Curves D. ph EFFECTS (3). Bell-Shaped Curves Example: Hydrolysis of aspirin. where 3 > l and " > '. The rae equaion is Some ph-rae profiles show maxima, ofen wih a "bell shaped" pea. rae [RCOOH][H+] + '[RCOOH] + "[RCOO-] + 3[RCOO-][OH-] The pka of aspirin is 3.6, so he plaeau region of he curve (ph 4 o 8) is accouned for primarily by he " erm, ha is, hydrolysis of he anion. This reacion is responsible for he insabiliy of aspirin in soluion dosage forms ph-rae profile for aspirin hydrolysis a 5 C 49 Hydrolysis of penicillin G caalyzed by 3,6-bis (dimehylaminomehyl)- caechol. Caalysis is produced by he monoanion of he caechol derivaive, 5 Vías de degraddación química Inhibición de la oxidación Hidrólisis Proeger de la luz Oxidación Eviar presencia oxígeno Racemización Uso agenes anioxidanes Descarboxilación Polimerización Descomposición enzimáica 5 5 3

14 Anioxidanes sisemas hidrófilos Anioxidanes sisemas lipófilos Combinaciones inorgánicas de azufre: sulfios (olor y sabor desagradables) Combinaciones orgánicas de azufre: (olor y sabor desagradables) Ácido ascórbico: ópicas, parenerales, orales Naurales: Tocoferoles Sinéicos y semisinéicos: Ácido gálico y éseres del ácido gálico Éseres ácido ascórbico Builhidroxianisol(BHA) Builhidroxiolueno(BHT) Sinérgicos Sobredosificación Reforzadores de acción: ácido fosfórico, ciríco, arárico Inacivadores de caalizadores: EDTA Anibióicos, viaminas Exceso de conenido acivo que es necesario ener en cuena para garanizar la esabilidad, es decir, la compensación de la pérdida de principio acivo previsa durane el periodo de conservación

15 Inesabilidad biológica Clasificación conservanes Conservadores: requisios Fenoles Tolerancia fisiológica Alcoholes alifáicos y aromáicos Compaibilidad Compuesos orgánicos de mercurio química Compuesos de amonio cuaernario Olor y sabor Ácidos carboxílicos Especro acivo Oros