Effect of Different Types of Polymers as Well as Different Preparation Techniques on the In-Vitro Release of Dyphylline Controlled Release Matrix Tablets

doi:10.21203/rs.3.rs-211212/v1

Dyphylline, xanthine derivatives, is used to manage asthma, cardiac dyspnea, chronic bronchitis, and emphysema. This work aimed to develop controlled release matrix tablets of Dyphylline using different types of polymers, and different preparation techniques such as direct compression, wet granulation, and hot melt methods. The prepared matrix tablets were evaluated by Infrared spectral analysis, differential thermal analysis, evaluation which included hardness, friability, content uniformity, and the in-vitro drug release. Kinetic analysis of the release profiles was investigated using different kinetic orders. All Dyphylline formulae obey Higuchi’s diffusion model. The diffusion is the mechanism of Dyphylline release from its controlled matrix tablets. IR and DSC revealed no incompatibility between Dyphylline and the polymers used in the prepared formulae. The obtained results revealed that the wet granulation technique using water as the granulating liquid is the best method for the formulation of Dyphylline hydrophilic matrix tablets compared with the other techniques. The high content of polymers led to the high value of T_1/2, and a decrease in Dyphylline's extent due to the improvement of the retention of drug release. A synergistic effect was obtained using PVP-K-25 in the hydrophilic matrix tablets, which led to the retention of the drug release.

Drug Discovery, Design, & Development

Materials Theory and Modeling

Clinical Pharmacology

Dyphylline

Wet granulation

Direct compression

Hot melts method

Controlled release system

Matrix tablets

Kinetic analysis.

Table (1): Composition of dyphylline controlled release matrix tablets prepared with different hydrophilic and hydrophobic polymers applying different methods of preparation

Formula code	Polymer type	Polymer conc. (%)
F₁	Xanthan gum	7%
F₂		14%
F₃		21%
F₄	Sodium alginate	7%
F₅		14%
F₆		21%
F₇	Alginic acid	7%
F₈		14%
F₉		21%
F₁₀	HPMC K100M CR	7%
F₁₁		14%
F₁₂		21%
F₁₃	HPMC E4M CR	7%
F₁₄		14%
F₁₅		21%
F₁₆	HPC	7%
F₁₇		14%
F₁₈		21%
F₁₉	HEC	7%
F₂₀		14%
F₂₁		21%
F₂₂	Compritol ATO 888	7%
F₂₃		14%
F₂₄		21%
F₂₅	Precirol ATO 5	7%
F₂₆		14%
F₂₇		21%

Table (2): Composition of dyphylline controlled release matrix tablets prepared with mixtures of hydrophilic polymers using wet granulation method and water as a granulating liquid

Formula number	Polymers ratio	Total polymer conc. (%)(%)
F_28Ww	Xanthan gum: HPMC K100M CR (1: 1)	21
F_29Ww	Xanthan gum: HPMC E4M CR (1: 1)	21
F_30Ww	Xanthan gum: HPC (1: 1)	21
F_31Ww	Xanthan gum: HEC (1: 1)	21

Table (3): Composition of dyphylline controlled release matrix tablets prepared with some hydrophilic polymers and adding 1% PVP K-25 as a binder using wet granulation and water as a granulating liquid

Formula code	Polymer type	Polymer conc. (%)
F_32Ww	Xanthan gum	14
F_33Ww	HPMC K100M CR	21
F_34Ww	HPMC E4M CR	21
F_35Ww	HPC	21
F_36Ww	HEC	21

The subscript d is added for tables prepared by direct compression, W_w for wet granulation with water, W_i for wet granulation with isopropyl alcohol, and H for hot melt method.

Table (4): Angle of repose of dyphylline tablet blends intended for preparation by direct compression.

Formula code	Angle of repose
F_1d	44
F_2d	45
F_3d	45
F_4d	42
F_5d	44
F_6d	44
F_7d	41
F_8d	43
F_9d	44
F_10d	36
F_11d	37
F_12d	38
F_13d	37
F_14d	39
F_15d	39
F_16d	36
F_17d	36
F_18d	38
F_19d	41
F_20d	41
F_21d	42
F_22d	42
F_23d	42
F_24d	43
F_25d	42
F_26d	42
F_27d	43

Table (5): Hardness, Friability and content of dyphylline controlled release matrix tablets prepared with different hydrophilic and hydrophobic polymers using direct compression method

Formula code	Hardness (kg)*	Friability (%)	Dyphylline content (mg)*
F_1d	14± 1.43	0.49	102 ± 2.11
F_2d	15± 1.65	0.67	100 ± 1.77
F_3d	15± 0.75	0.59	105 ± 1.15
F_4d	15± 1.01	0.58	105 ± 1.85
F_5d	15± 0.65	0.65	108 ± 2.02
F_6d	14± 1.44	0.58	102 ± 2.11
F_7d	15± 1.57	0.55	100 ± 1.77
F_8d	15± 0.59	0.49	102 ± 2.44
F_9d	15± 0.67	0.48	105 ± 1.99
F_10d	15± 0.88	0.49	104 ± 1.88
F_11d	15± 0.94	0.59	89 ± 3.75
F_12d	16± 0.46	0.58	104 ± 1.58
F_13d	15± 0.44	0.47	106 ± 1.96
F_14d	15± 0.56	0.63	105 ± 3.55
F_15d	15 ± 1.42	0.67	87 ± 2.66
F_16d	14± 0.85	0.56	108 ± 2.54
F_17d	16± 0.44	0.62	102 ± 3.11
F_18d	16± 0.75	0.53	104 ± 2.44
F_19d	15± 1.15	0.59	110 ± 3.24
F_20d	15± 1.12	0.65	111 ± 2.65
F_21d	14 ± 1.22	0.57	104 ± 1.10
F_22d	14 ± 1.25	0.56	102 ± 1.23
F_23d	14 ± 1.22	0.58	104 ± 1.65
F_24d	13 ± 1.34	0.63	97 ± 1.34
F_25d	14± 0.64	0.51	107 ± 3.81
F_26d	16± 1.13	0.61	96 ± 1.71
F_27d	16± 1.44	0.64	113 ± 1.72

٭(Mean ± SD, n=3).

Table (6): Optimum conditions for wet granulation

Factors		MDT (h.)
Granule size (μm)	780	1.149
	950	0.771
	1350	0.356
Compression force (kpsi)	8	0.987
	10	1.149
	12	1.522
Wetting agent volume (mg/tablet)	250	0.532
	300	0.954
	375	1.149
Punch	16 mm circular	0.876
	20 mm oblong plain	1.149
	20 mm oblong bisected	0.504

Table (7): Hardness, Friability and content of dyphylline controlled release matrix tablets prepared with different hydrophilic polymers using wet granulation method and water as a granulating liquid

Formula	Hardness (kg)*	Friability (%)	Dyphylline content (mg)*
F_1ww	17± 0.65	0.54	101 ± 2.41
F_2ww	14± 0.92	0.44	104 ± 1.10
F_3ww	8± 0.92	0.84	104 ± 1.10
F_4ww	14± 1.50	0.69	95 ± 1.71
F_5ww	15± 0.75	0.65	112 ± 1.92
F_6ww	15± 1.15	0.48	107 ± 3.87
F_7ww	15± 0.84	0.54	92 ± 1.85
F_8ww	14± 0.95	0.48	103 ± 2.21
F_9ww	16± 0.65	0.44	105 ± 2.92
F_10ww	15± 0.55	0.43	98 ± 2.29
F_11ww	15± 0.65	0.25	101 ± 3.27
F_12ww	15± 1.12	0.26	109 ± 1.95
F_13ww	16± 0.35	0.54	108 ± 2.12
F_14ww	15± 0.95	0.43	102 ± 2.44
F_15ww	15± 0.65	0.28	105 ± 1.99
F_16ww	15± 0.85	0.41	104 ± 1.88
F_17ww	15± 0.92	0.29	89 ± 3.75
F_18ww	16± 0.32	0.19	104 ± 1.58
F_19ww	15± 0.33	0.45	106 ± 1.96
F_20ww	15± 0.52	0.63	105 ± 3.55
F_21ww	13 ± 1.02	0.87	87 ± 2.60

٭(Mean ± SD, n=3).

Table (8): Hardness, Friability and content of Dyphylline controlled release matrix tablets prepared with different hydrophilic polymers using wet granulation method and isopropyl alcohol as a granulating liquid

Formula	Hardness (kg)*	Friability	Dyphylline content (mg)*
F_1wi	15± 1.25	0.64	101 ± 2.72
F_2wi	15± 1.11	0.58	105 ± 1.85
F_3wi	7.2± 0.55	0.75	108 ± 2.02
F_4wi	15± 1.15	0.61	101 ± 3.17
F_5wi	14± 1.53	0.59	102 ± 2.11
F_6wi	15± 1.75	0.65	100 ± 1.77
F_7wi	15± 0.85	0.58	105 ± 1.15
F_8wi	15± 1.11	0.57	87 ± 3.65
F_9wi	14± 0.75	0.55	103 ± 2.22
F_10wi	16± 1.44	0.61	101 ± 2.54
F_11wi	15± 1.22	0.41	104 ± 3.61
F_12wi	15± 1.13	0.39	110 ± 2.51
F_13wi	15± 1.36	0.31	104 ± 1.10
F_14wi	16± 0.25	0.55	102 ± 3.81
F_15wi	15± 1.14	0.50	95 ± 1.71
F_16wi	15± 0.55	0.42	112 ± 1.92
F_17wi	15± 0.64	0.49	107 ± 3.85
F_18wi	15± 0.86	0.38	103 ± 3.11
F_19wi	16± 1.32	0.30	101 ± 2.71
F_20wi	15± 1.15	0.59	110 ± 3.24
F_21wi	15± 1.12	0.68	111 ± 2.65

٭(Mean ± SD, n=3).

Table (9): Hardness, friability and content of dyphylline controlled release matrix tablets prepared with some hydrophilic polymers and adding extra binder as PVP K-25 1% using wet granulation with water as a granulating liquid

Formula	Hardness (kg) *	Friability (%)	Dyphylline content (mg)*
F_32Ww	16± 1.23	0.42	99 ± 1.76
F_33Ww	18 ± 0.97	0.28	96 ± 0.76
F_34Ww	15 ± 0.97	0.57	88 ± 2.71
F_35Ww	16 ± 1.56	0.32	103 ± 1.42
F_36Ww	17 ± 0.95	0.44	113 ± 2.01

٭(Mean ± SD, n=3).

Table (10): Hardness, friability and content of dyphylline controlled release matrix tablets prepared with some hydrophilic polymers and adding extra binder as PVP K-25 1% using wet granulation with water as a granulating liquid

Formula	Hardness (kg) *	Friability (%)	Dyphylline content (mg)*
F_32Ww	16± 1.23	0.42	99 ± 1.76
F_33Ww	18 ± 0.97	0.28	96 ± 0.76

F_34Ww	15 ± 0.97	0.57	88 ± 2.71
F_35Ww	16 ± 1.56	0.32	103 ± 1.42
F_36Ww	17 ± 0.95	0.44	113 ± 2.01

Table (11): Hardness, Friability and content of dyphylline controlled release matrix tablets prepared with different hydrophobic polymers using hot melt method.

Formula	Hardness (kg)*	Friability (%)	Dyphylline content (mg)*
F_22H	15± 0.94	0.59	99 ± 3.25
_F23H	16± 0.46	0.58	102 ± 2.58
F_24H	15± 0.44	0.46	100 ± 2.96
F_25H	15± 0.56	0.62	89 ± 3.33
F_26H	15 ± 1.42	0.68	94 ± 2.68
F_27H	14± 0.85	0.56	103 ± 3.54

٭(Mean ± SD, n=3).

Table (12): Kinetic analysis of the release data for the selected tablet formulae

Formula	Zero order			First order		Higuchi model			Korsemeyer peppas
Formula	R2	K	T50% (hours)	R²	K	R²	K	T50% (hours)	R²	n exponent
F_2Ww	0.969	7.975	6.055	0.569	11.301	0.994	28.304	6.032	0.980	0.659
F_12Ww	0.969	7.936	6.30	0.619	12.081	0.994	28.140	6.289	0.981	0.658
F_15Ww	0.984	7.838	6.141	0.601	13.022	0.985	28.489	6.212	0.994	0.693
F_18Ww	0.975	7.869	6.354	0.611	14.001	0.992	28.139	6.332	0.969	0.599
F_21Ww	0.969	7.969	6.274	0.597	11.008	0.994	28.258	6.256	0.979	0.662
F₂₄_D	0.969	7.942	6.132	0.611	12.042	0.994	28.160	6.098	0.980	0.657
F₂₄_H	0.968	7.990	6.044	0.621	13.005	0.994	28.325	6.103	0.980	0.671
F_28Ww	0.982	7.928	6.306	0.599	12.008	0.987	28.680	6.329	0.983	0.523
F_29Ww	0.992	7.721	6.476	0.597	11.804	0.978	28.481	6.498	0.990	0.692
F_33Ww	0.970	7.942	6.296	0.607	12.154	0.994	28.169	6.227	0.982	0.659
F_34Ww	0.983	7.949	6.290	0.591	11.985	0.990	28.682	6.297	0.648	0.768
F_36Ww	0.984	7.894	6.334	0.589	13.121	0.988	28.595	6.341	0.996	0.581
Data are mean ± SD; n=3, K is the release rate constant

No competing interests reported.

Effect of Different Types of Polymers as Well as Different Preparation Techniques on the In-Vitro Release of Dyphylline Controlled Release Matrix Tablets

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